Method of using calcilytic compounds

ABSTRACT

The present invention features calcilytic compounds. &#34;Calcilytic compounds&#34; refer to compounds able to inhibit calcium receptor activity. Also described are the use of calcilytic compounds to inhibit calcium receptor activity and/or achieve a beneficial effect in a patient; and techniques which can be used to obtain additional calcilytic compounds.

RELATED APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 08/629,608,filed Apr. 9, 1996, now abandoned, and a continuation-in-part ofprovisional application U.S. Ser. No. 60/032,263, filed Dec. 3, 1996.

FIELD OF THE INVENTION

The present invention relates to compounds able to inhibit calciumreceptor activity and the use of such compounds. Preferably, thecompounds described herein are administered to patients to achieve atherapeutic effect.

BACKGROUND OF THE INVENTION

Certain cells in the body respond not only to chemical signals, but alsoto ions such as extracellular calcium ions (Ca²⁺). Extracellular Ca²⁺ isunder tight homeostatic control and regulates various processes such asblood clotting, nerve and muscle excitability, and proper boneformation.

Calcium receptor proteins enable certain specialized cells to respond tochanges in extracellular Ca²⁺ concentration. For example, extracellularCa²⁺ inhibits the secretion of parathyroid hormone (PTH) fromparathyroid cells, inhibits bone resorption by osteoclasts, andstimulates secretion of calcitonin from C-cells.

PTH is the principal endocrine factor regulating Ca²⁺ homeostasis in theblood and extracellular fluids. PTH, by acting on bone and kidney cells,increases the level of Ca²⁺ in the blood. This increase in extracellularCa²⁺ then acts as a negative feedback signal, depressing PTH secretion.The reciprocal relationship between extracellular Ca²⁺ and PTH secretionforms an important mechanism maintaining bodily Ca²⁺ homeostasis.

Extracellular Ca²⁺ acts directly on parathyroid cells to regulate PTHsecretion. The existence of a parathyroid cell surface protein whichdetects changes in extracellular Ca²⁺ has been confirmed. (Brown et al.,Nature 366:574, 1993.) In parathyroid cells, this protein, the calciumreceptor, acts as a receptor for extracellular Ca²⁺, detects changes inthe ion concentration of extracellular Ca²⁺, and initiates a functionalcellular response, PTH secretion.

Extracellular Ca²⁺ can exert effects on different cell functions,reviewed in Nemeth et al., Cell Calcium 11:319, 1990. The role ofextracellular Ca²⁺ in parafollicular (C-cells) and parathyroid cells isdiscussed in Nemeth, Cell Calcium 11:323, 1990. These cells were shownto express similar calcium receptors. (See, Brown et al., Nature366:574, 1993; Mithal et al., J. Bone Miner. Res. 9, Suppl. 1, s282,1994; Rogers et al., J. Bone Miner. Res. 9, Suppl, 1, s409, 1994;Garrett et al., Endocrinology 136:5202-5211, 1995.) The role ofextracellular Ca²⁺ on bone osteoclasts is discussed by Zaidi, BioscienceReports 10:493, 1990.

The ability of various molecules to mimic extracellular Ca²⁺ in vitro isdiscussed in references such as Nemeth et al., in "Calcium-BindingProteins in Health and Disease," 1987, Academic Press, Inc., pp. 33-35;Brown et al., Endocrinology 128:3047, 1991; Chen et al., J. Bone Miner.Res. 5:581, 1990; and Zaidi et al., Biochem. Biophys. Res. Commun.167:807, 1990.

Nemeth et al., PCT/US92/07175, International Publication Number WO93/04373, Nemeth et al., PCT/US93/01642, International PublicationNumber WO 94/18959, and Nemeth et al., PCT/US94/12117, InternationalPublication Number WO 95/11211, feature calcium receptor-activemolecules and refer to calcilytics as compounds able to inhibit calciumreceptor activity. For example, WO 94/18959 on page 8, lines 2-13asserts:

Applicant is also the first to describe methods by which moleculesactive at these Ca²⁺ receptors can be identified and used as leadmolecules in the discovery, development, design, modification and/orconstruction of useful calcimimetics or calcilytics which are active atCa²⁺ receptors. Such calcimimetics or calcilytics are useful in thetreatment of various disease states characterized by abnormal levels ofone or more components, e.g., polypeptides such as hormones, enzymes orgrowth factors, the expresssion and/or secretion of which is regulatedor affected by activity at one or more Ca²⁺ receptors.

The references provided in the background are not admitted to be priorart to the pending claims.

SUMMARY OF THE INVENTION

The present invention features calcilytic compounds. "Calcilyticcompounds" refer to compounds able to inhibit calcium receptor activity.The ability of a compound to "inhibit calcium receptor activity" meansthat the compound causes a decrease in one or more calcium receptoractivities evoked by extracellular Ca²⁺.

The use of calcilytic compounds to inhibit calcium receptor activityand/or achieve a beneficial effect in a patient are described below.Also described below are techniques which can be used to obtainadditional calcilytic compounds.

An example of featured calcilytic compounds are Structure Iα,α-disubstituted arylalkylamine derivatives having the chemicalformula: ##STR1## where R₁ is selected from the group consisting of:aryl, longer-length alk, and cycloalk;

R₂ is selected from the group consisting of: lower alk, cycloalk,alkoxy, H, OH, ═O, C(O)OH, C(O)O-lower alk, C(O)NH-lower alk,C(O)N(lower alk)₂, SH, S-lower alk, NH₂, NH-lower alk, and N(lower alk)₂;

R₃ and R₄ is each independently lower alk or together cyclopropyl;

R₅ is aryl;

R₆ if present is either hydrogen, lower alkyl or lower alkenyl, whereinR₆ is not present if R₂ is ═O;

Y₁ is either covalent bond, alkylene, or alkenylene;

Y₂ is alkylene;

Y₃ is alkylene; and

Z is selected from the group consisting of: covalent bond, O, S, NH,N-lower alk, alkylene, alkenylene, and alkynylene, provided that if Z iseither O, S, NH, or N-lower alk, then Y₁ is not a covalent bond, furtherprovided that Y₁ and Z may together be a covalent bond;

and pharmaceutically acceptable salts and complexes thereof.

The terms aryl, longer-length alk, lower alk, cycloalk, alkoxy,alkylene, alkenylene, and alkynylene, along with possible substituentsare defined in Section II, infra. Section II, infra, also providesdefinitions for other chemical groups described in the presentapplication.

Preferred calcilytic compounds have an IC₅₀ ≦50 μM, more preferably anIC₅₀ <10 μM, and even more preferably an IC₅₀ <1 μM, as measured usingthe "Calcium Receptor Inhibitor Assay" described in Example 1, infra.

Thus, a first aspect of the present invention features a method oftreating a patient by administering to the patient a therapeuticallyeffective amount of a Structure I α,α-disubstituted arylalkylaminederivative. Treatment can be carried out, for example, to retard thedisease in a patient having a disease or to prophylactically retard orprevent the onset of a disease.

A therapeutically effective amount is the amount of compound whichachieves a therapeutic effect by retarding a disease in a patient havinga disease or prophylactically retarding or preventing the onset of adisease. Preferably, it is an amount which relieves to some extent oneor more symptoms of a disease or disorder in a patient; returns tonormal either partially or completely one or more physiological orbiochemical parameters associated with or causative of the disease ordisorder; and/or reduces the likelihood of the onset of the disease ofdisorder.

A "patient" refers to a mammal in which compounds characterized by theirability to inhibit calcium receptor activity, in vivo or in vitro, willhave a beneficial effect. Preferably, the patient is a human being.

Patients benefiting from the administration of a therapeutic amount of acalcilytic compound can be identified using standard techniques known tothose in the medical profession. Diseases or disorders which can betreated by inhibiting one or more calcium receptor activities includeone or more of the following types: (1) those characterized by anabnormal bone and mineral homeostasis; (2) those characterized by anabnormal amount of an extracellular or intracellular messenger whoseproduction can be affected by one or more calcium receptor activities;(3) those characterized by an abnormal effect (e.g., a different effectin kind or magnitude) of an intracellular or extracellular messengerwhich can itself be ameliorated by one or more calcium receptoractivities; and (4) other diseases or disorders where inhibition of oneor more calcium receptor activities exerts a beneficial effect, forexample, in diseases or disorders where the production of anintracellular or extracellular messenger stimulated by receptor activitycompensates for an abnormal amount of a different messenger. Examples ofextracellular messengers whose secretion and/or effect can be affectedby inhibiting calcium receptor activity are believed to includeinorganic ions, hormones, neurotransmitters, growth factors, andchemokines. Examples of intracellular messengers include cAMP, cGMP,IP₃, calcium, magnesium, and diacylglycerol.

Preferably, a patient is a human having a disease or disordercharacterized by one or more of the following: (1) an abnormal bone ormineral homeostasis; (2) an abnormal amount of an extracellular orintracellular messenger which is ameliorated by a compound able toeffect one or more calcium receptor activities; and (3) an abnormaleffect of an intracellular or extracellular messenger which isameliorated by a compound able to effect one or more calcium receptoractivities.

Preferably, the disease or disorder is characterized by an abnormal boneand mineral homeostasis, more preferably calcium homeostasis. Abnormalcalcium homeostasis is characterized by one or more of the followingactivities: (1) an abnormal increase or decrease in serum calcium; (2)an abnormal increase or decrease in urinary excretion of calcium; (3) anabnormal increase or decrease in bone calcium levels, for example, asassessed by bone mineral density measurements; (4) an abnormalabsorption of dietary calcium; (5) an abnormal increase or decrease inthe production and/or release of messengers which affect serum calciumlevels such as PTH and calcitonin; and (6) an abnormal change in theresponse elicited by messengers which affect serum calcium levels. Theabnormal increase or decrease in these different aspects of calciumhomeostasis is relative to that occurring in the general population andis generally associated with a disease or disorder.

Preferably, the calcilytic compounds are used to treat diseases ordisorders selected from the group consisting of: hypoparathyroidism,osteosarcoma, periodontal disease, fracture healing, osteoarthritis,rheumatoid arthritis, Paget's disease, humoral hypercalcemia malignancy,and osteoporosis.

Another aspect of the present invention describes a method of treating apatient comprising the step of administering to the patient an amount ofa calcilytic compound sufficient to increase serum PTH level.Preferably, the method is carried out by administering an amount of thecompound effective to cause an increase in duration and/or quantity ofserum PTH level sufficient to have a therapeutic effect.

Increasing serum PTH may be used to achieve a therapeutic effect byretarding a disease in a patient having the disease or prophylacticallyretarding or preventing the onset of a disease. Prophylactic treatmentcan be performed, for example, on a person with an abnormally low serumPTH; or on a person without a low serum PTH, but were increasing PTH hasa beneficial effect. An abnormally low serum PTH is a serum PTH levellower than that occurring in the general population, and is preferablyan amount associated with a disease or the onset of a disease.

Increasing serum PTH levels can be used to treat different types ofdiseases including bone and mineral related diseases.

In different embodiments, the compound administered to a patient causesan increase in serum PTH having a duration up to one hour, about one toabout twenty-four hours, about one to about twelve hours, about one toabout six hours, about one to about five hours, about one to about fourhours, about two to about five hours, about two to about four hours, orabout three to about six hours.

In additional different embodiments, the compound administered to apatient causes an increase in serum PTH up to 0.5 fold, 0.5 to 5 fold, 5fold to 10 ten fold, and at least 10 fold, greater than peak serum PTHin the patient. The peak serum level is measured with respect to thepatient not undergoing treatment.

Another aspect of the present invention features Structure I calcilyticcompounds.

Another aspect of the present invention features a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acalcilytic compound described herein. The pharmaceutical compositioncontains the calcilytic compound in a form suitable for administrationinto a mammal, preferably, a human being. Preferably, the pharmaceuticalcomposition contains an amount of a calcilytic compound in a properpharmaceutical dosage form sufficient to exert a therapeutic effect on ahuman being. However, multiple doses of pharmaceutical compositions maybe used to treat a patient.

Considerations and factors concerning dosage forms suitable foradministration are known in the art and include potential toxic effects,solubility, route of administration, and maintaining activity. Forexample, pharmaceutical compositions injected into the bloodstreamshould be soluble.

Another aspect of the present invention features a method of screeningfor Structure I α,α-disubstituted arylalkylamine derivatives able toinhibit calcium receptor activity. The method involves the steps ofcontacting a cell having a calcium receptor with a Structure Iα,α-disubstituted arylalkylamine derivative and measuring the ability ofthe compound to inhibit calcium receptor activity.

The screening method can be carried out in vivo or in vitro and isparticularly useful to identify those Structure I α,α-disubstitutedarylalkylamine derivatives most able to act as calcilytic compounds. Invivo assays include measuring a physiological parameter related tocalcium receptor activity, such as serum hormone levels or serum calciumion concentration. In vitro assays include measuring the ability of thecalcilytic compound to affect intracellular calcium concentration, orcellular hormone secretion. Examples of hormones levels which can beaffected by calcilytic compounds include PTH and calcitonin.

The calcilytic compounds described herein can be used as part of in vivoor in vitro methods. Preferably, the compounds are used in vivo toachieve a beneficial effect in a patient. Examples of in vitro uses, andother in vivo uses, include use in a method to identify other calcilyticcompounds and use as a tool to investigate calcium receptor activity orthe physiological effects of inhibiting calcium receptor activity indifferent organisms.

Other features and advantages of the invention will be apparent from thefollowing detailed description of the invention, examples, and theclaims.

DETAILED DESCRIPTION OF THE INVENTION

The present application demonstrates the ability of calcilytic compoundsto exert a physiologically relevant effect on a cell by illustrating theability of such compounds to increase PTH secretion and also identifiesa target site for calcilytic compounds. The present application isbelieved to be the first to demonstrate that calcilytic compounds canincrease PTH secretion.

Calcium receptors are present on different cell types and can regulatedifferent responses in different cell types. While the calcilyticcompounds described herein are believed to act at a calcium receptorthrough a calcium receptor-activity modulating site, unless otherwiseexplicitly stated in the claims that a compound exerts an effect byacting at a calcium receptor through such a site, there is no intentionto limit the claimed methods or compound to requiring inhibition ofcalcium receptor activity or any particular mode of action. Rather, thepresent application demonstrates that compounds able to inhibit calciumreceptor activity, whose calcilytic activity can be measured in vivo orin vitro, exert significant physiological effects. For example, thepresent application demonstrates the ability of different calcilyticcompounds to prevent Ca²⁺ inhibition of PTH and, thereby, result in anincrease in PTH release.

Compounds binding at the calcium receptor-activity modulating site canbe identified using a labeled compound binding to the site in acompetition-binding assay format.

Preferred calcilytic compounds described herein are Structure Iα,α-disubstituted arylalkylamine derivatives able to inhibit calciumreceptor activity. Other aspects of the present invention include assayswhich can be used to identify those Structure I α,α-disubstitutedarylalkylamine derivatives expected to be effective in inhibitingcalcium receptor activity, and/or exerting a therapeutic effect in apatient; preferred groups of Structure I α,α-disubstitutedarylalkylamine derivatives; and the use of the compounds describedherein to treat different diseases or disorders.

I. Calcium Receptor Activity

Calcium receptors respond to changes in extracellular calcium levels.The exact changes resulting from calcium receptor activity depend on theparticular receptor and the cell containing the receptor. For example,the in vitro effect of calcium on the calcium receptor in a parathyroidcell includes the following:

1. An increase in internal calcium [Ca²⁺ ]_(i). The increase is due tothe influx of external calcium and/or to the mobilization of internalcalcium. Characteristics of the increase in internal calcium include thefollowing:

(a) A rapid (time to peak <5 seconds) and transient increase in [Ca²⁺]_(i) that is refractory to inhibition by 1 μM La³⁺ or 1 μM Gd³⁺ and isabolished by pretreatment with ionomycin (in the absence ofextracellular Ca²⁺);

(b) The increase is not inhibited by dihydropyridines;

(c) The transient increase is abolished by pretreatment for 10 minuteswith 10 mM sodium fluoride;

(d) The transient increase is diminished by pretreatment with anactivator of protein kinase C (PKC), such as phorbol myristate acetate(PMA), mezerein or (-)-indolactam V. The overall effect of the proteinkinase C activator is to shift the concentration-response curve ofcalcium to the right without affecting the maximal response; and

(e) Pretreatment with pertussis toxin (100 ng/ml for >4 hours) does notaffect the increase. 2. A rapid (<30 seconds) increase in the formationof inositol-1,4,5-triphosphate and/or diacylglycerol. Pretreatment withpertussis toxin (100 ng/ml for >4 hours) does not affect this increase;

3. The inhibition of dopamine- and isoproterenol-stimulated cyclic AMPformation. This effect is blocked by pretreatment with pertussis toxin(100 ng/ml for >4 hours); and

4. The inhibition of PTH secretion. Pretreatment with pertussis toxin(100 ng/ml for >4 hours) does not affect the inhibition of PTHsecretion.

Calcilytic activity of a compound can be determined using techniquessuch as those described in the examples below and those described inpublications such as Nemeth et al., PCT/US92/07175, InternationalPublication Number WO 93/04373, Nemeth et al., PCT/US93/01642,International Publication Number WO 94/18959, and Nemeth et al.,PCT/US94/12117, International Publication Number WO 95/11211 (each ofwhich are hereby incorporated by reference herein).

Calcilytic activity varies depending upon the cell type in which theactivity is measured. For example, calcilytic compounds possess one ormore, and preferably all, of the following characteristics when testedon parathyroid cells in vitro:

1. The compound blocks, either partially or completely, the ability ofincreased concentrations of extracellular Ca²⁺ to:

(a) increase [Ca²⁺ ]_(i),

(b) mobilize intracellular Ca²⁺,

(c) increase the formation of inositol-1,4,5-triphosphate,

(d) decrease dopamine- or isoproterenol-stimulated cyclic AMP formation,and

(e) inhibit PTH secretion;

2. The compound blocks increases in Cl⁻ current in Xenopus oocytesinjected with poly(A)⁺ -mRNA from bovine or human parathyroid cellselicited by extracellular Ca²⁺, but not in Xenopus oocytes injected withwater; and

3. Similarly, the compound blocks a response in Xenopus oocytes,injected with cloned nucleic acid expressing the calcium receptor,elicited by extracellular Ca2+ or a calcimimetic compound (i.e., acompound able to mimic the effect of extracellular Ca²⁺, includingcompounds potentiating the effect of extracellular Ca²⁺).

Calcium receptors are present in different cells. The pharmacologicaleffects of the following cells, in response to extracellular Ca²⁺, isconsistent with the presence of a calcium receptor: parathyroid cell,bone osteoclast, juxtaglomerular kidney cell, proximal tubule kidneycell, distal tubule kidney cell, central nervous system cell, peripheralnervous system cell, cell of the thick ascending limb of Henle's loopand/or collecting duct, keratinocyte in the epidermis, parafollicularcell in the thyroid (C-cell), intestinal cell, trophoblast in theplacenta, platelet, vascular smooth muscle cell, cardiac atrial cell,gastrin-secreting cell, glucagon-secreting cell, kidney mesangial cell,mammary cell, endocrine and exocrine cells in the pancreas, fat/adiposecell, immune cell, GI tract cell, skin cell, adrenal cell, pituitarycell, hypothalamic cell and cell of the subfornical organ.

The presence of a calcium receptor on the following cells have beenconfirmed using physical data, such as hybridization with nucleic acidencoding a calcium receptor: parathyroid cell, central nervous systemcell, peripheral nervous system cell, cell of the thick ascending limbof Henle's loop and/or collecting duct in the kidney, parafollicularcell in the thyroid (C-cell), intestinal cell, GI tract cell, pituitarycell, hypothalamic cell, cell of the subfornical organ, and endocrineand exocrine cells in the pancreas.

II. α,α-Disubstituted Arylalkylamine Derivatives

Structure I α,α-disubstituted arylalkylamine derivatives have thefollowing chemical formula: ##STR2## where R₁ is selected from the groupconsisting of: aryl, longer-length alk, and cycloalk. Preferably, R₁ iseither optionally substituted phenyl, optionally substituted pyridyl,optionally substituted benzothiopyranyl, optionally substitutedcarbazole, optionally substituted naphthyl, optionally substitutedtetrahydronaphthyl, optionally substituted longer-length alkyl,optionally substituted longer-length alkenyl or optionally substitutedcycloalk.

More preferably, R₁ is either an optionally substituted phenyl; anoptionally substituted naphthyl; an optionally substituted pyridyl; anoptionally substituted benzothiopyranyl; an optionally substitutedcarbazole; unsubstituted longer-length alkyl; unsubstitutedlonger-length alkenyl; or monosubstituted longer-length alkyl oralkenyl, where the monosubstituent is either an optionally substitutedphenyl or an optionally substituted cycloalkyl provided that theoptionally substituted phenyl or optionally substituted cycloalkyl canhave one to four substituents each independently selected from the groupconsisting of: alkoxy, lower-haloalkyl, S-unsubstituted alkyl,lower-haloalkoxy, unsubstituted alkyl, unsubstituted alkenyl, halogen,SH, CN, NO₂, NH₂ and OH;

R₂ is selected from the group consisting of: lower alk, cycloalk,alkoxy, H, OH, ═O, C(O)OH, C(O)O-lower alk, C(O)NH-lower alk,C(O)N(lower alk)₂, SH, S-lower alk, NH₂, NH-lower alk, and N(loweralk)₂. More preferably, R₂ is OH or alkoxy, even more preferably, R₂ isOH or methoxy;

R₃ and R₄ is each independently lower alk or together cyclopropyl.Preferably, R₃ and R₄ are each independently a lower alkyl, morepreferably, R₃ and R₄ are each independently methyl or ethyl;

R₅ is aryl. Preferably, R₅ is either optionally substituted naphthyl oroptionally substituted phenyl. More preferably, R₅ is substituted phenylhaving a substituent in the meta or para position and optionallycontaining additional substituents;

R₆ if present is either hydrogen, lower alkyl or lower alkenyl, whereinR₆ is not present if R₂ is ═O. Preferably R₆ is either hydrogen or loweralkyl, more preferably R₆ is hydrogen.

Y₁ is either covalent bond, alkylene, or alkenylene. Preferably, Y₁ iseither covalent bond or lower alkylene. More preferably, Y₁ ismethylene;

Y₂ is alkylene. Preferably, Y₂ is lower alkylene. More preferably, Y₂ ismethylene;

Y₃ is alkylene. Preferably, Y₃ is lower alkylene. More preferably, Y₃ ismethylene;

Z is selected from the group consisting of: covalent bond, O, S, NH,N-lower alk, alkylene, alkenylene, and alkynylene, provided that if Z iseither O, S, NH, or N-lower alk, then Y₁ is not a covalent bond, furtherprovided that Y₁ and Z may together be a covalent bond. Preferably, Z isselected from the group consisting of: covalent bond, O, S, NH, N-loweralk, and alkylene. More preferably, Z is either O, S, lower alkylene,even more preferably, Z is O;

and pharmaceutically acceptable salts and complexes thereof.

"Alk" refers to either alkyl, alkenyl, or alkynyl. "Lower alk" refers toeither lower alkyl, lower alkenyl, or lower alkynyl, preferably, loweralkyl.

"Alkenyl" refers to an optionally substituted hydrocarbon groupcontaining at least one carbon-carbon double bond between the carbonatoms and containing 2-15 carbon atoms joined together. The alkenylhydrocarbon group may be straight-chain or contain one or more branches.Branched- and straight-chain alkenyl preferably have 2 to 7 carbons,each of which may be optionally substituted. Alkenyl substituents areeach independently selected from the group consisting of: lower alkyl,lower alkenyl, halogen, alkoxy, lower haloalkyl, lower haloalkoxy,methylene dioxy, unsubstituted aryl, unsubstituted cycloalkyl, OH, SH,CN, NO, NO₂, NH₂, CH═NNHC(O)NH₂, CH═NNHC(S)NH₂, CH₂ O-lower alkyl,C(O)lower alkyl, C(O)NH₂, C(O)NH-lower alkyl, C(O)N(lower alkyl)₂,C(O)OH, C(O)O-lower alkyl, NH-lower alkyl, N(lower alkyl)₂,NHC(O)unsubstituted aryl, NHC(O)lower alkyl, N═N-unsubstituted aryl,NHC(O)NH₂, N(lower alkyl)C(O)lower alkyl, NHC(S)lower alkyl, N(loweralkyl)C(S)lower alkyl, NHS(O)lower alkyl, N(lower alkyl)S(O)lower alkyl,OC(O)lower alkyl, OCH₂ C(O)OH, OC(S)lower alkyl, S(O)lower alkyl,SC(O)lower alkyl, S-lower alkyl, S-lower haloalkyl, SO₂ -lower alkyl,SO₂ -lower haloalkyl, S(O)₂ NH₂, S (O)₂ NH-lower alkyl, and S(O)₂N(lower alkyl)₂. Preferably, no more than three substituents arepresent. Even more preferably, the alkenyl is a lower alkenyl, which isan unsubstituted branched- or straight-chain alkenyl having 2 to 4carbons.

"Alkyl" refers to an optionally substituted hydrocarbon group joined bysingle carbon-carbon bonds and having 1-15 carbon atoms joined together.The alkyl hydrocarbon group may be straight-chain or contain one or morebranches. Branched- and straight-chain alkyl preferably have 1 to 7carbons, each of which may be optionally substituted. Alkyl substituentsare each independently selected from the substituents described abovefor alkenyl. Preferably, no more than three substituents are present.More preferably, the alkyl is a lower alkyl, which is an unsubstitutedbranched- or straight-chain alkyl 1 to 4 carbons in length.

"Alkynyl" refers to an optionally substituted hydrocarbon groupcontaining at least one carbon-carbon triple bond between the carbonatoms and containing 2-15 carbon atoms joined together. The alkynylhydrocarbon group may be straight-chain or contain one or more branches.Branched- and straight-chain alkynyl preferably have 2 to 7 carbons,each of which may be optionally substituted. Alkynyl substituents areeach independently selected from the substituents described above foralkenyl. Preferably, no more than three substituents are present. Morepreferably, the alkynyl is a lower alkynyl, which is an unsubstitutedbranched- or straight-chain alkynyl having 2 to 4 carbons.

"Alkenylene" refers to an optionally substituted hydrocarbon chaincontaining at least one carbon-carbon double bond between the carbonatoms. The alkenylene chain has 2 to 6 carbons and is attached at twolocations to other functional groups or structural moieties. Thealkenylene substituents are each independently selected from thesubstituents described above for alkenyl. Preferably, no more than threesubstituents are present. More preferably, the alkenylene is a "loweralkenylene," which is an unsubstituted branched- or straight-chainalkenylene having 2 to 3 carbons.

"Alkoxy" refers to oxygen joined to an unsubstituted alkyl 1 to 12carbon atoms in length, preferably 1 to 2 carbons in length. Morepreferably, the alkoxy is methoxy.

"Alkylene" refers to an optionally substituted hydrocarbon chaincontaining only carbon-carbon single bonds between the carbon atoms. Thealkylene chain has 1 to 6 carbons and is attached at two locations toother functional groups or structural moieties. The alkylenesubstituents are each independently selected from the substituentsdescribed above for alkenyl. Preferably, no more than three substituentsare present. More preferably, the alkylene is a "lower alkylene," whichis an unsubstituted branched- or straight-chain alkylene having 1 to 3carbons.

"Alkynylene" refers to an optionally substituted hydrocarbon chaincontaining at least one carbon-carbon triple bond between the carbonatoms. The alkynylene chain has 2 to 6 carbons and is attached at twolocations to other functional groups or structural moieties. Thealkynylene substituents are each independently selected from thesubstituents described above for alkenyl. More preferably, thealkynylene is a "lower alkynylene," which is an unsubstituted branched-or straight-chain alkynylene having 2 to 3 carbons.

"Aryl" refers to an optionally substituted aromatic group with at leastone ring having a conjugated pi- electron system, containing up to twoconjugated or fused ring systems. Aryl includes carbocyclic aryl,heterocyclic aryl and biaryl groups, all of which may be optionallysubstituted. Preferably, the aryl is either optionally substitutedphenyl, optionally substituted pyridyl, optionally substitutedbenzothiopyranyl, optionally substituted carbazole, optionallysubstituted naphthyl, optionally substituted tetrahydronaphthyl.

Different substituents are preferred for the Structure I left hand R₁aryl and the Structure I R₅ right hand aryl. Preferably, the aryl has nomore than five independently selected substituents.

Preferably, when R₁ is an aryl, the aryl is either optionallysubstituted phenyl, optionally substituted pyridyl, optionallysubstituted benzothiopyranyl, optionally substituted carbazole,optionally substituted naphthyl, or optionally substitutedtetrahydronaphthyl. Preferred, R₁ substituents are each independentlyselected from the group consisting of: unsubstituted alkyl,unsubstituted alkenyl, halogen, alkoxy, lower haloalkyl, lowerhaloalkoxy, methylene dioxy, unsubstituted aryl, unsubstitutedcycloalkyl, OH, SH, CN, NO, NO₂, NH2, methylene dioxy, CH═NNHC(O)NH₂,CH═NNHC(S)NH₂, CH₂ O-unsubstituted alkyl, C(O)unsubstituted alkyl,C(O)NH₂, C(O)NH-unsubstituted alkyl, C(O)N(unsubstituted alkyl)₂,C(O)OH, C(O)O-unsubstituted alkyl, NH-unsubstituted alkyl,N(unsubstituted alkyl)₂, NHC(O)unsubstituted aryl, NHC(O)unsubstitutedalkyl, N═N-unsubstituted aryl, NHC(O)NH₂, N(unsubstitutedalkyl)C(O)unsubstituted alkyl, NHC(S)unsubstituted alkyl,N(unsubstituted alkyl)C(S)unsubstituted alkyl, NHS(O)unsubstitutedalkyl, N(unsubstituted alkyl)S(O)unsubstituted alkyl, NS(O)₂ aryl,OC(O)unsubstituted alkyl, OCH₂ C(O)OH, OC(S) unsubstituted alkyl,S(O)unsubstituted alkyl, SC(O)unsubstituted alkyl, S-unsubstitutedalkyl, S-unsubstituted haloalkyl, SO₂ -unsubstituted alkyl, SO₂-unsubstituted haloalkyl, S(O)₂ NH₂, S(O)₂ NH-unsubstituted alkyl, andS(O)₂ N(unsubstituted alkyl)₂.

Preferred R₁ aryl substituents are each independently selected from thegroup consisting of: alkoxy, methylene dioxy, N(CH₃)₂, C(O)OCH₃, phenyl,lower-haloalkyl, S-unsubstituted alkyl, lower-haloalkoxy, unsubstitutedalkyl, unsubstituted alkenyl, halogen, SH, CN, NO₂, NH2, OH andsulfamoyl. More preferably, each R₁ aryl substituent is independentlyselected from the group consisting of: unsubstituted C₁ -C₇ alkyl, C₁-C₇ alkoxy, lower haloalkoxy, CF₃, F, Cl, Br, CN, NO₂ and sulfamoyl.

In another preferred embodiment, R₁ is either 2-CN-phenyl, 2,3-dichlorophenyl, 2-nitro-phenyl, 2-cyano-3-chloro-phenyl, or2,3-dichloro-4-sulfamoyl-phenyl.

R₅ right hand aryl substituents are each independently selected from thesubstituents described above for alkenyl. In a preferred embodiment, theR₅ aryl substituents are each independently selected from the groupconsisting of: methoxy, lower alkyl, lower haloalkoxy, CFH₂, CHF₂, CF₃,OCH₂ CF₃, F, Cl, Br, I, OH, SH, CN, NO₂, NH2, methylene dioxy, NH-loweralkyl, N(lower alkyl)₂, C(O)lower alkyl, S-lower alkyl, S(O)lower alkyl,S(O)₂ N lower alkyl, OC(O)lower alkyl, SC(O)lower alkyl, OC(S)loweralkyl, NHC(O)lower alkyl, N(lower alkyl)C(O)lower alkyl, NHC(S)loweralkyl, N(lower alkyl)C(S)lower alkyl, NHS(O)lower alkyl, N(loweralkyl)S(O)lower alkyl, C(O)OH, C(O)O-lower alkyl, C(O)NH₂, C(O)NH-loweralkyl, C(O)N(lower alkyl)₂, S(O)₂ NH₂, S(O)₂ NH-lower alkyl, and S(O)₂N(lower alkyl)₂.

In another preferred embodiment, R₅ aryl substituents are eachindependently selected from the group consisting of: methylene dioxy,methoxy, lower-haloalkyl, S-lower alkyl, lower-haloalkoxy, lower alkyl,halogen, SH, CN, OH, Cl, F, and Br. Preferred halogens are Cl, F, andBr.

"Carbocyclic aryl" refers to an aromatic ring or ring system having allcarbon atoms. The carbon atoms are optionally substituted.

"Cycloalk" refers to an optionally substituted cyclic alkyl or anoptionally substituted non-aromatic cyclic alkenyl and includesmonocyclic and multiple ring structures such as bicyclic and tricyclic.The cycloalk has 3 to 15 carbon atoms, preferably, 5 to 12 carbon atoms.Optional substituents for the cycloalk are each independently selectedfrom the group described above for alkenyl. Preferably, no more thanthree substituents are present. More preferably, the cycloalk isunsubstituted, even more preferably it is an unsubstituted cyclic alkyl.Preferred cycloalkyl groups include cyclohexyl and adamantyl.

"Haloalk" refers to substituted alkyl or substituted alkenyl, having nomore than 4 carbons, where the substituents are halogens and at leastone halogen is present. Preferably, the haloalk is an alkyl 1 to 3carbons in length and the halogens are each independently either Cl orF, more preferably the alkyl has 2 carbons, more preferably thehaloalkyl is a lower haloalkyl which has 1 carbon.

"Heterocyclic aryl" refers to an aryl having 1 to 3 heteroatoms as ringatoms in the aromatic ring and the remainder of the ring atoms arecarbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen.Examples of heterocyclic aryl include indolyl, pyridyl, quinolinyl, andisoquinolinyl.

"Longer-length alk" refers to either longer-length alkyl, longer-lengthalkenyl, or longer-length alkynyl; preferably, longer-length alkyl orlonger-length alkenyl. More preferably a longer-length alk is 4 to 20carbon atoms.

"Longer-length alkenyl" refers to an optionally substituted hydrocarbongroup containing at least one carbon-carbon double bond between thecarbon atoms, and which contains 2-20 carbon atoms joined together.Preferably, the longer-length alkenyl is 4 to 20 carbon atoms. Thelonger-length alkenyl hydrocarbon group may be straight-chain or containone or more branches. Longer-length alkenyl substituents are eachindependently selected from the alkenyl substituent list describedabove. Preferably, the longer-length alkenyl is either unsubstituted orhas one cycloalk or phenyl substituent. More preferably, the cycloalksubstituent, if present, is unsubstituted, and more preferably thecycloalk substituent, if present, is either cyclohexyl or adamantyl.

"Longer-length alkyl" refers to an optionally substituted hydrocarbongroup joined by single carbon-carbon bonds and which contains 1-20carbon atoms joined together. Preferably, the longer-length alkyl is 4to 20 carbon atoms. The longer-length alkyl hydrocarbon group may bestraight-chain or contain one or more branches. Longer-length alkylsubstituents are each independently selected from the alkenylsubstituent list described above. Preferably, the longer-length alkyl iseither unsubstituted or has one cycloalk or phenyl substituent. Morepreferably, the cycloalk substituent, if present, is unsubstituted, andmore preferably the cycloalk substituent, if present, is eithercyclohexyl or adamantyl.

"Longer-length alkynyl" refers to an optionally substituted hydrocarbongroup containing at least one carbon-carbon triple bond between thecarbon atoms, and which contains 2-20 carbon atoms joined together.Preferably, the longer-length alkynyl is 4 to 20 carbon atoms. Thelonger-length alkynyl hydrocarbon group may be straight-chain or containone or more branches. Longer-length alkynyl substituents are eachindependently selected from the alkenyl substituent list describedabove. Preferably, the longer-length alkynyl is either unsubstituted orhas one cycloalk or phenyl substituent substituent. More preferably, thecycloalk substituent, if present, is unsubstituted, and more preferablythe cycloalk substituent, if present, is either cyclohexyl or adamantyl.

"Haloalkoxy" refers to oxygen joined to a "haloalk." Preferably, thehaloalkoxy is a "lower-haloalkoxy," which is an oxygen joined to alower-haloalkyl.

A. α,α-Disubstituted β-Phenethylamine Derivatives

More preferred calcilytic compounds are Structure I derivatives whereR₁, R₂, R₃, R₄, R₆, Z, Y₁ and Y₂ are as described above for Structure Iα,α-disubstituted arylalkylamine derivatives, including preferred groups(see, Section II, supra); and

R₅ is either phenyl substituted with one to four independently selectedsubstituents or an optionally substituted naphthyl having up to fourindependently selected substituents. R₅ substituents are provided inSection II, supra., including preferred embodiments. More preferably R₅is either a substituted phenyl comprising a substituent in a meta orpara position, more preferably, the substituent present in a meta orpara position is either methyl, ethyl, isopropyl, methoxy, Cl, F, Br, orlower haloalkoxy.

The activity of different calcilytic compounds was measured using theCalcium Receptor Assay described below. Examples of compounds having anIC₅₀ ≦50 μM include compounds 1, 9, 17, 25, 29, 42, 56, 79, 90, 101 and164; examples of preferred compounds having an IC₅₀ <10 μM includecompounds 2, 3, 7, 8, 26, 27, 32, 33, 35, 37, 39, 41, 45, 48, 49, 59,61, 66, 68, 71, 75, 93, 98, 103, 104, 110, 111, 114, 123, 124, 125, 128,132, 144, 147, 152, 155, 158, 161, 162, 169 and 170; and examples ofmore preferred compounds having an IC₅₀ < than 1 μM include compounds 5,6, 19, 20, 21, 28, 38, 40, 43, 44, 46, 47, 50, 51, 63, 64, 65, 67, 69,72, 74, 96, 105, 106, 109, 112, 113, 115, 116, 117, 118, 119, 120, 121,122, 126, 127, 129, 130, 131, 133, 134, 135, 136, 137, 138, 139, 140,141, 142, 143, 145, 146, 148, 149, 150, 151, 153, 154, 156, 157, 159,160, 163, 165, 166, 167, and 168.

B. Structure II Compounds

Structure II compounds have the following structure: ##STR3##

In one embodiment R₁, R₂, R₃, and R₄ are as described above forStructure I α,α-disubstituted arylalkylamine derivatives, includingpreferred groups (see, Section II, supra); and

R₅ is either an optionally substituted naphthyl having one to foursubstituents independently selected from the group consisting of methyl,ethyl, isopropyl, methoxy, Cl, F, Br, or lower haloalkoxy, preferablythe naphthyl is unsubstituted; or a substituted phenyl having one tofour substituent with at least one substituent in a meta or paraposition selected from the group consisting of: lower alkyl, methoxy,Cl, F, Br, and lower haloalkoxy, more preferably a methoxy is present inthe para or meta position; even more preferably, the remaining R₅substituents are independently selected from the group consisting of:methoxy, lower-haloalkyl, S-lower alkyl, lower-haloalkoxy, lower alkyl,halogen, SH, CN, OH, Cl, F, and Br.

provided that R₁ is not 6-CN-2-pyridyl; and

further provided that if R₅ is 3,4 dimethoxy-phenyl, then R₁ is not CH₃(CH₂)₅ O-phenyl; 2-cyclopentyl-phenyl; 2-Cl-phenyl; 2-CN-phenyl;2-(3-furanyl)phenyl; or 4-(1,2,-benzisothiazol); preferably, R₅ is not3,4 dimethoxy phenyl;

further provided that if R₅ is 4-methoxy-phenyl, then R₁ is not2-cyclopentyl-phenyl; 2-CH₃ -phenyl; 2-benzyl-phenyl; 3-CH₃, 4-CH₃ SO₂-phenyl; or 4-(1,2,-benzisothiazol);

further provided that if R₅ is 4-Cl-phenyl, then R₁ is not 2-CH₃-phenyl, 5-iso-propyl-phenyl; 2-CH₃ -phenyl; 4-CH₃ -phenyl; phenyl;2-Cl-phenyl; 4-Cl-phenyl; 2-methoxy, 4-CH₃ CHCH-phenyl; 3,4 CH₃ -phenyl;2,4 CH₃ -phenyl; 2,3 CH₃ -phenyl; 2-iso-propyl, 5-CH₃ -phenyl; pridyl;or 1-imidazole; 4-(1,2,-benzisothiazol); preferably, R₄ is either not4-Cl, or R₄ is 3,4 dichlorophenyl; and

further provided that if R₅ is 3,5, dimethyl, 4-methoxyphenyl, then R₁is not 4-CH₃, 6-CN-2-pyridyl; or thiophenecarboxamide; preferably, R₅ isnot 3,5, dimethyl, 4-methoxy-phenyl.

In another embodiment, R₂, R₃, and R₄ are as described above forStructure I α,α-disubstituted arylalkylamine derivatives, includingpreferred groups (see, Section II, supra);

R₅ is either an optionally substituted naphthyl having one to foursubstituents independently selected from the group consisting of methyl,ethyl, isopropyl, methoxy, Cl, F, Br, and lower haloalkoxy, preferablythe naphthyl is unsubstituted; or a substituted phenyl having one tofour substituent with at least one substituent in a meta or paraposition selected from the group consisting of: methyl, ethyl,isopropyl, methoxy, Cl, F, Br, and lower haloalkoxy, more preferably amethoxy is present in the para or meta position; even more preferably,the remaining R₅ substituents are independently selected from the groupconsisting of: methoxy, lower-haloalkyl, S-lower alkyl,lower-haloalkoxy, lower alkyl, halogen, SH, CN, OH, Cl, F, and Br; and

R₁ is either 2-CN-phenyl, 2,3-dichloro phenyl, 2-nitrophenyl,2-cyano-3-chloro-phenyl, 2,3-dichloro-4-sulfamoylphenyl, an optionallysubstituted pyridyl, an optionally substituted benzothiopyranyl, or anoptionally substituted carbazole, where the optionally presentsubstituents for the pyridyl, benzothiopyranyl, and carbazole asdescribed in Section II supra, for aryl R₁ substituents, includingpreferred substituents, and are even more preferably independentlyselected from the group consisting of: methoxy, lower-haloalkyl, S-loweralkyl, lower-haloalkoxy, lower alkyl, halogen, SH, CN, OH, Cl, F, Br andsulfamoyl.

C. R₂ -group Stereochemistry

The different calcilytic compounds described herein can have differentstereochemistry around different groups. In an embodiment of the presentinvention the Structure I compounds have the following absoluteconfiguration structure with respect to R₂ : ##STR4## III.Pharmaceutical Composition

The calcilytic compounds described herein can be formulated as apharmaceutical composition to facilitate the administration of thecompound to a patient. Preferred formulations contain a pharmaceuticallyacceptable carrier and a calcilytic compound as described in Section II,supra., including the different embodiments.

Examples of suitable carriers are provided below, in Section V,"Administration," and include calcium carbonate, calcium phosphate,lactose, glucose, sucrose, gelatin, vegetable oils, polyethylene glycolsand physiologically compatible solvents.

IV. Treatment of Diseases or Disorders

Compounds inhibiting calcium receptor activity can be used to conferbeneficial effects to patients suffering from a variety of diseases ordisorders. Diseases or disorders which can be treated using a calcilyticcompound are known in the art and can be identified using the presentapplication as a guide. For example, diseases or disorders can beidentified based on the functional responses of cells regulated bycalcium receptor activity.

Diseases and disorders which can be treated using the calcilyticcompounds described herein include those due to different cellulardefects related to calcium receptor activity in different cells, such asa defective calcium receptor or an abnormal number of calcium receptors,a defective intracellular protein acted on by a calcium receptor, or adefective protein or an abnormal number of proteins acting on a calciumreceptor.

Functional responses of cells regulated by the calcium receptor areknown in the art, including PTH secretion by parathyroid cells,calcitonin secretion by C-cells, bone resorption by osteoclasts, andCa²⁺ secretion by kidney cells. Such functional responses are associatedwith different diseases or disorders.

For example, isolated osteoclasts respond to increases in theconcentration of extracellular Ca²⁺ with corresponding increases in[Ca²⁺ ]_(i) arising partly from the mobilization of intracellular Ca²⁺.Increases in [Ca²⁺ ]_(i) in osteoclasts are associated with theinhibition of bone resorption.

Renin secretion from juxtaglomerular cells in the kidney is depressed byincreased concentrations of extracellular Ca²⁺. Extracellular Ca²⁺causes the mobilization of intracellular Ca²⁺ in these cells. Otherkidney cells respond to extracellular Ca²⁺ as follows: elevated Ca²⁺inhibits formation of 1,25(OH)₂ -vitamin D by proximal tubule cells,stimulates production of calcium-binding protein in distal tubule cells,and inhibits tubular reabsorption of Ca²⁺ and Mg²⁺ in the thickascending limb of Henle's loop (MTAL), and reduces vasopressin action inthe cortical collecting duct.

Other examples of functional responses affected by extracellular Ca²⁺include promoting differentiation of intestinal goblet cells, mammarycells, and skin cells; inhibiting atrial natriuretic peptide secretionfrom cardiac atria; reducing cAMP accumulation in platelets; alteringgastrin and glucagon secretion; acting on perivascular nerves to modifycell secretion of vasoactive factors; and affecting cells of the centralnervous and peripheral nervous systems.

Diseases and disorders which might be treated or prevented, based uponthe affected cells, include bone and mineral-related diseases ordisorders; hypoparathyroidism; those of the central nervous system suchas seizures, stroke, head trauma, spinal cord injury, hypoxia-inducednerve cell damage, such as occurs in cardiac arrest or neonataldistress, epilepsy, neurodegenerative diseases such as Alzheimer'sdisease, Huntington's disease and Parkinson's disease, dementia, muscletension, depression, anxiety, panic disorder, obsessive-compulsivedisorder, post-traumatic stress disorder, schizophrenia, neurolepticmalignant syndrome, and Tourette's syndrome; diseases involving excesswater reabsorption by the kidney, such as syndrome of inappropriate ADHsecretion (SIADH), cirrhosis, congestive heart failure, and nephrosis;hypertension; preventing and/or decreasing renal toxicity from cationicantibiotics (e.g., aminoglycoside antibiotics); gut motility disorderssuch as diarrhea and spastic colon; GI ulcer diseases; GI diseases withexcessive calcium absorption such as sarcoidosis; autoimmune diseasesand organ transplant rejection; squamous cell carcinoma; andpancreatitis.

While calcilytic compounds of the present invention will typically beused to treat human patients, they may also be used to treat similar oridentical diseases or disorders in other warm-blooded animal species,such as other primates, farm animals such as swine, cattle, and poultry;and sports animals and pets such as horses, dogs and cats.

Preferably, calcilytic compounds are used in the treatment of bone andmineral-related diseases or disorders. Bone and mineral-related diseasesor disorders comprise a diverse class of disorders affecting nearlyevery major organ system in the body. Examples of bone andmineral-related diseases or disorders include osteosarcoma, periodontaldisease, fracture healing, osteoarthritis, rheumatoid arthritis, Paget'sdisease, humoral hypercalcemia malignancy, and osteoporosis. Morepreferably, calcilytic compounds are used to treat osteoporosis, adisease characterized by reduced bone density and an increasedsusceptibility to fractures. Osteoporosis is associated with aging,especially in women.

One way of treating osteoporosis is by altering PTH secretion. PTH canhave a catabolic or an anabolic effect on bone. Whether PTH causes acatabolic effect or an anabolic effect seems to depend on how plasmalevels of PTH are altered. When plasma levels of PTH are chronicallyelevated, as in hyperparathyroid states, there is a net loss of bone. Incontrast, intermittent increases in plasma PTH levels, as achieved byadministration of exogenous hormone, result in new bone formation.Anabolic action of PTH on bone is described, for example, by Dempster etal., Endocrin. Rev. 14:690-709, 1993.

As demonstrated by the Examples provided below, calcilytic compoundsstimulate secretion of PTH. Such calcilytic compounds can be used toincrease bone formation in a patient, for example, by intermittentdosing, thus achieving intermittent increases in the circulating levelsof PTH.

V. Administration

The calcilytic compounds described by the present invention can beformulated for a variety of modes of administration, including systemicand topical or localized administration. Techniques and formulationsgenerally may be found in Remington's Pharmaceutical Sciences, 18^(th)ed., Mack Publishing Co., Easton, Pa., 1990 (hereby incorporated byreference herein).

Suitable dosage forms, in part, depend upon the use or the route ofentry, for example, oral, transdermal, transmucosal, or by injection(parenteral). Such dosage forms should allow the compound to reach atarget cell whether the target cell is present in a multicellular hostor in culture. For example, pharmacological compounds or compositionsinjected into the blood stream should be soluble. Other factors areknown in the art, and include considerations such as toxicity and dosageforms which retard the compound or composition from exerting its effect.

Compounds can also be formulated as pharmaceutically acceptable saltsand complexes thereof. Pharmaceutically acceptable salts are non-toxicsalts in the amounts and concentrations at which they are administered.The preparation of such salts can facilitate the pharmacological use byaltering the physical characteristics of the compound without preventingit from exerting its physiological effect. Useful alterations inphysical properties include lowering the melting point to facilitatetransmucosal administration and increasing the solubility to facilitateadministering higher concentrations of the drug.

The pharmaceutically acceptable salt of the different compounds may bepresent as a complex. Examples of complexes include an8-chlorotheophylline complex (analogous to, e.g.,dimenhydrinate:diphenhydramine 8-chlorotheophylline (1:1) complex;Dramamine) and various cyclodextrin inclusion complexes.

Pharmaceutically acceptable salts include acid addition salts such asthose containing sulfate, hydrochloride, fumarate, maleate, phosphate,sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate,cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts canbe obtained from acids such as hydrochloric acid, maleic acid, sulfuricacid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lacticacid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamicacid, fumaric acid, and quinic acid.

Pharmaceutically acceptable salts also include basic addition salts suchas those containing benzathine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, procaine, aluminum, calcium, lithium,magnesium, potassium, sodium, ammonium, alkylamine, and zinc, whenacidic functional groups, such as carboxylic acid or phenol are present.For example, see Remington's Pharmaceutical Sciences, 18^(th) ed., MackPublishing Co., Easton, Pa., p. 1445, 1990. Such salts can be preparedusing the appropriate corresponding bases.

Pharmaceutically acceptable salts can be prepared by standardtechniques. For example, the free-base form of a compound is dissolvedin a suitable solvent, such as an aqueous or aqueous-alcohol in solutioncontaining the appropriate acid and then isolated by evaporating thesolution. In another example, a salt is prepared by reacting the freebase and acid in an organic solvent. (See, e.g., PCT/US92/03736, herebyincorporated by reference herein.)

Carriers or excipients can also be used to facilitate administration ofthe compound. Examples of carriers include calcium carbonate, calciumphosphate, various sugars such as lactose, glucose, or sucrose, or typesof starch, cellulose derivatives, gelatin, vegetable oils, polyethyleneglycols and physiologically compatible solvents. Examples ofphysiologically compatible solvents include sterile solutions of waterfor injection (WFI), saline solution and dextrose.

The calcilytic compounds can be administered by different routesincluding intravenous, intraperitoneal, subcutaneous, intramuscular,oral, topical (transdermal), or transmucosal administration. Forsystemic administration, oral administration is preferred. For oraladministration, for example, the compounds can be formulated intoconventional oral dosage forms such as capsules, tablets, and liquidpreparations such as syrups, elixirs, and concentrated drops.

Alternatively, injection (parenteral administration) may be used, e.g.,intramuscular, intravenous, intraperitoneal, and subcutaneous. Forinjection, the compounds of the invention are formulated in liquidsolutions, preferably, in physiologically compatible buffers orsolutions, such as saline solution, Hank's solution, or Ringer'ssolution. In addition, the compounds may be formulated in solid form andredissolved or suspended immediately prior to use. Lyophilized forms canalso be produced.

Systemic administration can also be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art, and include, forexample, for transmucosal administration, bile salts and fusidic acidderivatives. In addition, detergents may be used to facilitatepermeation. Transmucosal administration, for example, may be throughnasal sprays, rectal suppositories, or vaginal suppositories.

For topical administration, the compounds of the invention can beformulated into ointments, salves, gels, or creams, as is generallyknown in the art.

The amounts of various calcilytic compounds to be administered can bedetermined by standard procedures taking into account factors such asthe compound IC₅₀, EC₅₀, the biological half-life of the compound, theage, size and weight of the patient, and the disease or disorderassociated with the patient. The importance of these and other factorsto be considered are known to those of ordinary skill in the art.Generally, it is an amount between about 0.1 and 50 mg/kg, preferably0.01 and 20 mg/kg of the animal to be treated.

VI. Examples

The examples provided below, like the other examples provided herein,are not intended to limit the claimed invention, but rather illustratedifferent aspects and embodiments of the present invention.

EXAMPLE 1: Calcium Receptor Inhibitor Assay

This example illustrates the use of the Calcium Receptor InhibitorAssay. Calcilytic activity was measured by determining the IC₅₀ of thetest compound for blocking increases of intracellular Ca²⁺ elicited byextracellular Ca²⁺ in HEK 293 4.0-7 cells stably expressing the humancalcium receptor. HEK 293 4.0-7 cells were constructed as described byRogers et al., J. Bone Miner. Res. 10 Suppl. 1:S483, 1995 (herebyincorporated by reference herein). Intracellular Ca²⁺ increases wereelicited by increasing extracellular Ca²⁺ from 1 to 1.75 mM.Intracellular Ca²⁺ was measured using fluo-3, a fluorescent calciumindicator.

The procedure was as follows:

1. Cells were maintained in T-150 flasks in selection media (DMEMsupplemented with 10% fetal bovine serum and 200 μg/mL hygromycin B),under 5% CO₂ :95% air at 37° C. and were grown up to 90% confluency.

2. The medium was decanted and the cell monolayer was washed twice withphosphate-buffered saline (PBS) kept at 37° C. After the second wash, 6mL of 0.02% EDTA in PBS was added and incubated for 4 minutes at 37° C.Following the incubation, cells were dispersed by gentle agitation.

3. Cells from 2 or 3 flasks were pooled and pelleted (100×g). Thecellular pellet was resuspended in 10-15 mL of SPF-PCB+ and pelletedagain by centrifugation. This washing was done twice.

Sulfate- and phosphate-free parathyroid cell buffer (SPF-PCB) contains20 mM Na-Hepes, pH 7.4, 126 mM NaCl, 5 mM KCl, and 1 mM MgCl₂. SPF-PCBwas made up and stored at 4° C. On the day of use, SPF-PCB wassupplemented with 1 mg/mL of D-glucose and 1 mM CaCl₂ and then splitinto two fractions. To one fraction, bovine serum albumin (BSA; fractionV, ICN) was added at 5 mg/mL (SPF-PCB+). This buffer was used forwashing, loading and maintaining the cells. The BSA-free fraction wasused for diluting the cells in the cuvette for measurements offluorescence.

4. The pellet was resuspended in 10 mL of SPF-PCB+ containing 2.2 μMfluo-3 (Molecular Probes) and incubated at room temperature for 35minutes.

5. Following the incubation period, the cells were pelleted bycentrifugation. The resulting pellet was washed with SPF-PCB+. Afterthis washing, cells were resuspended in SPF-PCB+ at a density of 1-2×10⁶cells/mL.

6. For recording fluorescent signals, 300 μL of cell suspension werediluted in 1.2 mL of SPF buffer containing 1 mM CaCl₂ and 1 mg/mL ofD-glucose. Measurements of fluorescence were performed at 37° C. withconstant stirring using a spectrofluorimeter. Excitation and emissionwavelengths were measured at 485 and 535 nm, respectively. To calibratefluorescence signals, digitonin (5 mg/mL in ethanol) was added to obtainF_(max), and the apparent F_(min) was determined by adding Tris-EGTA(2.5M Tris-Base, 0.3M EGTA). The concentration of intracellular calciumwas calculated using the following equation: Intracellularcalcium=(F-F_(min) /F_(max))×Kd; where Kd=400 nM.

7. To determine the potential calcilytic activity of test compounds,cells were incubated with test compound (or vehicle as a control) for 90seconds before increasing the concentration of extracellular Ca²⁺ from 1to 2 mM. Calcilytic compounds were detected by their ability to block,in a concentration-dependent manner, increases in the concentration ofintracellular Ca²⁺ elicited by extracellular Ca²⁺.

In general, those compounds having lower IC₅₀ values in the CalciumReceptor Inhibitor Assay are more preferred compounds. Compounds havingan IC₅₀ greater than 50 AM were considered to be inactive. Preferredcompounds are those having an IC₅₀ 10-50 μM, more preferred compoundshave an IC₅₀ 1-10 μM, and most preferred compounds have an IC₅₀ lessthan 1 μM.

Examples of compounds having an IC₅₀ greater than 50 μM includecompounds 22, 24, 34, 36, 52, 53, 54, 55, 58, 60, 62, 70, 84, 92, 99,and 102.

EXAMPLE 2: Adrenergic Receptor Activity

Structure I α,α-disubstituted arylalkylamine derivatives includecompounds which have both calcilytic activity and β-adrenergic receptoractivity. If desired, β-adrenergic activity can be reduced usingappropriate functional groups and structural modifications.Modifications which can be carried out to reduce β-adrenergic receptoractivity include using alternative R₂ groups and using absolutestereochemistry opposite to that which occurs in active β-adrenergicreceptor antagonists, which provides compounds corresponding to the Renantiomer when R₂ is OH. β-adrenergic receptor activity and binding tothe β-adrenergic receptor can be measured using standard techniques. Forexample, see Riva et al., Mol. Pharmacol. 36:201-210, 1989.

In one embodiment of the present invention the calcilytic compounds havean IC₅₀ ≧1.0 nM, at the β-adrenergic receptor as measured using the"β-Adrenergic Receptor Binding Assay" described below. In otherembodiments, using the β-Adrenergic Receptor Assay calcilytic compoundshave an IC₅₀ ≧1.0 μM, and IC₅₀ ≧10.0 μM.

The "β-Adrenergic Receptor Binding Assay" is carried out as follows:Incubations are performed in polypropylene reaction tubes in a 37° C.water bath. To each tube 50 μL of test sample is added, followed by 300μL of assay buffer (50 mM Tris-HCl, pH 7.5), and 50 μL of 20 nM [³H]-dihydroalprenolol. The binding reaction is initiated by the additionof 100 μL of 3.75 mg/mL well-washed rat cortex membranes in assaybuffer, and allowed to incubate at 37° C. for 30 minutes. Non-specificbinding is determined in the presence of 10 μM alprenolol. The finalconcentration of reactants is: 2 nM [³ H]-dihydroalprenolol, and 75mg/mL rat cortex membrane in a reaction volume of 0.5 mL.

The binding reaction is terminated by rapid filtration with ice-coldassay buffer onto GF/C filters (Brandel, Gaithersburg, Md.) which havebeen soaked for 15 minutes in assay buffer. The reaction is firstdiluted with 3 mL of cold assay buffer (4° C.), then aspirated onto thefilter followed by 3×3 mL washes. Filter disks are placed in 7-mLpolypropylene scintillation vials with 5 mL of ScintiSafe 50% (FisherScientific, Pittsburgh, Pa.), and counted overnight.

EXAMPLE 3: Stimulation of PTH Secretion

This example illustrates the ability of different calcilytic compoundsto exert a biological effect on PTH secretion. PTH secretion wasdetermined using dissociated bovine parathyroid cells as described belowfor Compounds 32, 33, and 38. Compounds 32, 33, and 38 all stimulatedPTH secretion with an EC₅₀ of less than 10 μM.

Stimulation of PTH secretion was assayed as follows:

Preparation of Dissociated Bovine Parathyroid Cells

Parathyroid cell buffer (PCB) contains (mM): NaCl, 126; KCl, 4; MgSO₄,1; K₂ HPO₄ /KH₂ PO₄, 0.7; Na-Hepes, pH 7.45, and variable amounts ofCaCl₂ as specified (reagent grade). PCB was typically supplemented withbovine serum albumin (BSA fraction V; ICN Biomedicals, Inc., Costa Mesa,Calif.; catalog #81-003) and 1 mg/mL of D-glucose (reagent grade) asindicated. Percoll purification buffer was prepared immediately beforeuse by mixing 8 mL of Percoll (Pharmacia LKB, Alameda, Calif.; catalog#17-0891-01) and 7 mL of a twice-concentrated PCB solution withoutphosphate and containing 2 mM CaCl₂.

Parathyroid glands were obtained from calves within minutes of slaughterat an abattoir and shipped via overnight express on ice in PCBcontaining 1.25 mM CaCl₂. The glands were trimmed and minced in ice-coldPCB containing 1.25 mM CaCl₂, 1 mg/mL of D-glucose, and 2% BSA.Dissociated cells were obtained by collagenase digestion by vigorouslyshaking the minced tissue at 37° C. in PCB containing 0.5 to 1.0%Collagenase P (Boehringer Mannheim, Indianapolis, Ind.; catalog #1249002), 2 to 5 units of deoxyribonuclease (Sigma, St. Louis, Mo.; catalog#D-0876), 1 mg/mL of D-glucose, and 1.25 mM CaCl₂ (reagent grade). Thecell suspension was triturated at 30 minute intervals using 25- and10-mL pipettes as the minced tissue was digested and the cells weredispersed.

Cells were pooled at 1-hour intervals by filtering the cell suspensionthrough a 250-μm Nitex screen into 15-mL polystyrene centrifuge tubesand spinning at 100×g for 5 minutes at 22° C. The pooled cell pellet wasresuspended in Percoll purification buffer and purified bycentrifugation at 14,500×g for 20 minutes at 4° C. Dissociatedparathyroid cells equilibrated within a buoyant density of 1.048-1.062above a dense band of red blood cells and below a diffuse band thatcontains adipocytes, strands of collagen, and damaged cells.

The dissociated parathyroid cells were removed with a sterile pipetteand washed 3 to 4 times under sterile conditions in a 1:1 mixture ofHam's F-12 and Dulbecco's modified Eagle's medium (F-12/DMEM, Sigma, St.Louis, Mo.; catalog #D 8900) supplemented with 0.5% BSA, 100 U/mL ofpenicillin, 100 μg/mL of streptomycin (Gibco BRL, Grand Island, N.Y.;catalog #15140-031), and 20 μg/mL of gentamicin (Sigma, St. Louis, Mo.;catalog #G 1397).

The cells were finally resuspended in F-12/DMEM supplemented with lowerantibiotic concentrations (10 U/mL of penicillin, 10 μg/mL ofstreptomycin, and 4 μg/mL of gentamicin). This latter medium lacks serumand contained ITS⁺ (insulin, transferrin, selenous acid, BSA, andlinoleic acid; Collaborative Biomedical Products, Bedford, Mass.;catalog #40352).

Cells were incubated in T-75 flasks at 37° C. in a humid atmosphere of5% CO₂ in air. Parathyroid cells were collected for use by decanting theflasks after 18 to 24 hours in primary culture. The concentrations ofgentamicin and streptomycin used here are considerably below the EC₅₀for mobilization of intracellular calcium (150 and 600 μM,respectively).

Measurement of Parathyroid Hormone (PTH) Secretion

Sulfate, phosphate-free parathyroid cell buffer (SPF-PCB) contains (mM):NaCl, 126; KCl, 5; MgCl₂, 1; Na-Hepes, pH 7.45, and variable amounts ofCaCl₂ as specified (reagent grade). SPF-PCB was typically supplementedwith bovine serum albumin (BSA fraction V; ICN Biomedicals, Inc., CostaMesa, Calif.; catalog #81-003) and 1 mg/mL of D-glucose (reagent grade)as indicated.

Incubations were performed in triplicate in 12×75 mm polypropylene orpolystyrene tubes to which were added 2.5 μL of test compound. The tubeswere kept on ice until the drug additions were completed, then weretransferred to a water bath at 37° C., and the reactions were initiatedby the addition of 0.2 mL of a suspension of dissociated cells at adensity of 1 to 2 million cells/mL in SPF-PCB containing 0.5 mM Ca²⁺, 1mg/mL of D-glucose, and 0.1% BSA. Incubation was for 30 minutes and thereaction was terminated by placing the tubes on ice. Cells were pelletedby gentle centrifugation (500×g for 10 minutes at 4° C.) and 0.1 mL ofsupernatant was removed and stored at -20° C.

Amino-terminal bovine PTH was measured by radioimmunoassay (RIA) usinggoat anti-hPTH antiserum H₂, HPLC-purified ¹²⁵ I-hPTH (1-34) and bovinePTH (1-84) standards. Serial dilutions of bPTH standards (1,000 pg/25 μLto 3.8 pg/25 μL) were done in 50 mM Tris, pH 7.4, containing 0.5 mM Naazide and 2% bovine serum albumin (diluent). Standards and samples wereincubated for 2-3 days at 4° C. in the presence of antiserum after which1,500-2,000 cpm label/tube was added. After an additional incubation for1 to 2 days at 4° C., dextran-coated charcoal was added to separatebound vs. free label. The contents of each tube were mixed and thecharcoal was pelleted by centrifugation. The supernatants were decantedinto 12×75 mm polystyrene tubes and counted in a Packard Cobra gammacounter.

EXAMPLE 4: General Procedures for the Preparation of CalcilyticCompounds

The calcilytic compounds described by the present invention can beprepared using standard techniques. For example, an overall strategy forpreparing preferred compounds described herein can be carried out asdescribed in this section. The examples which follow illustrate thesynthesis of specific compounds. Using the protocols described herein asa model, one of ordinary skill in the art can readily produce otherStructure I compounds.

All reagents and solvents were obtained from commercial vendors.Starting materials (e.g., amines and epoxides) were synthesized usingstandard techniques and procedures. GC/El-MS (GasChromatographic/Electron-Impact Mass Spectrometric) analyses wereperformed on HP-5890 Series II gas chromatographs equipped withHP-Ultra-2 or HP-5MS columns (30 mm×0.25 mm ID) and HP-5971 or HP-5972Mass Selective Spectrometric Detectors (MSD's) were used. MPLC(Medium-Pressure Liquid Chromatography) separations were carried out onsilica gel (400 mesh) using an FMI pump, ISCO UV-6 detector (254 nm) andFOXY 200 fraction collector. HPLC (High Performance LiquidChromatography) was performed using RAININ HP-XL pumps and Dynamix UV-1detectors (254 mm).

Examples of specific separation conditions and details are given in theindividual experimental descriptions provided in the examples below.Chiral HPLC separations were carried out using a Beckman System GoldHPLC and UV detector (254 nm) on Diacel® ChiralCel OD columns (ChiralTechnologies, Inc., Exton, Pa. 19341).

NMR (Nuclear Magnetic Resonance) spectroscopy was performed on a VarianGemini 300 spectrometer. Proton and carbon spectra were taken at 300 MHzand 75 MHz, respectively. NMR resonances are reported in ppm relative totetramethylsilane (TMS) with the following descriptors for the observedmultiplicities: s (singlet), d (doublet), t (triplet), q (quartet), dd(doublet of doublets) and m (multiplet). J_(AB) coupling constants arereported in Hz. Elemental analyses were performed and FT-IR data wereacquired by Oneida Research Services, Inc., Whitesboro, N.Y. 13492.

A general procedure used to synthesize many of the compounds was carriedout as follows: A solution of glycidyl ether (i.e.,1,2-epoxy-3-phenoxypropane, 1 mmol) and excess amine (typically1,1-dimethyl-2-(4-methoxyphenyl)ethylamine, 1.5 mmol) in absoluteethanol (2 mL) is stirred overnight at 50°-60° C. The product ispurified by one of three general methods: (1) conversion to thehydrochloride salt, followed by Reversed-Phase High-Performance LiquidChromatography (RP-HPLC, 0.1% HCl/acetonitrile); (2) conversion to thehydrochloride salt, followed by recrystallization from water-methanol oracetonitrile; and (3) purification by normal-phase chromatography(column chromatography or preparative, thin-layer chromatography (TLC)).Hydrochloride salts were also prepared by treatment of the correspondingfree base in diethyl ether with 1M HCl (in diethyl ether).

EXAMPLE 5: Preparation ofN-[2-Hydroxy-3-(1-naphthoxy)propyl]-1,1-dimethyl-2-(4-fluorophenyl)ethylamine Hydrochloride, Compound 2 ##STR5##

A stirred suspension of sodium hydride (4.0 g of 60% NaH in mineral oil,100 mmol) in dimethylformamide (DMF, 100 ml) was treated with 1-naphthol(14.42 g, 100 mmol). After stirring for 1 hour at ambient temperature(room temperature), the reaction was treated with epichlorohydrin (10.18g, 110 mmol) and stirred for 1 hour at 100° C. The reaction was dilutedwith water and transferred to a separatory funnel using diethyl ether(500 ml). The organic phase was washed with 10% aqueous NaHCO₃ (3×200ml), dried over anhydrous sodium sulfate, filtered, and concentrated.Kugelrohr distillation (˜100 microns) yielded 1-naphthyl glycidyl etheras a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 200 (M⁺, 61), 184(1), 169 (5), 157 (12), 144 (79), 129 (16), 115 (100), 101 (3), 89 (16).

A stirred solution of 1-naphthyl glycidyl ether (400 mg, 2 mmol) and1,1-dimethyl-2-(4-fluorophenyl)ethylamine (334 mg, 2 mmol) in absoluteethanol (2 mL) was heated at 50-60° C. for 16 hours. Chromatography ofthe resulting reaction mixture through silica (5×30 cm) using a gradientof chloroform to 5% methanol in chloroform afforded the free base of thetitle compound: GC/EI-MS, m/z (rel. int.) 368 (M.sup. 1, 1), 352 (2),258 (100), 183 (5), 157 (4), 127 (5), 115 (18), 109 (23), 71 (30).

The free base in diethyl ether was treated with excess 1M HCl (diethylether). The resulting solid was recrystallized from hot acetonitrile toafford 300 mg of the title compound as a crystalline solid: ¹ H-NMR(DMF-D₇) δ 9.9 (1H, br s), 9.5 (1H, br s), 8.33 (1H, d, J=9), 7.91 (1H,d, J=9), 7.57-7.50 (3H, m), 7.48-7.41 (3H, m), 7.19 (2H, t, J=10), 7.03(1H, d, J=7), 6.37 (1H, br d, J=5), 4.67 (1H, br s), 4.31 (2H, br t,J=6), 3.61 (1H, br t), 3.42 (1H, br t), 3.31 (2H, s), 1.47 (3H, s), 1.46(3H, s); ¹³ C-NMR (DMF-D₇) δ 161.5, 158.2, 152.2, 132.5, 130.8, 130.7,129.7, 125.4, 124.4, 124.1, 124.5, 120.0, 118.3, 113.1, 112.8, 103.1,68.1, 64.2, 57.9, 43.5, 40.3, 20.2.

EXAMPLE 6: Preparation ofN-(2-Hydroxy-3-phenoxypropyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 3 ##STR6##

A cooled (-78 ° C.) solution of diisopropylamine (65 g, 642 mmol) intetrahydrofuran (THF, 800 mL) was treated with 244 mL of 2.5M n-butyllithium (610 mmol) in hexane. The reaction was stirred for 30 minutes atroom temperature, cooled to -78° C. and treated dropwise with isobutyricacid (26.8 g, 305 mmol) and hexamethylphosphoramide (HMPA, 54.7 g, 305mmol). The reaction was stirred for 30 minutes at room temperature andtreated with 4-methoxybenzyl chloride (43.4 g, 277 mmol). The reactionwas stirred for 48 hours at room temperature and treated with 10% HCl(200 mL). The reaction was concentrated to 300 mL and diluted to 600 mLwith water. The resulting solution was extracted with diethyl ether(2×300 mL) and the combined ether extracts were washed with 10% HCl(2×200 mL). The ether extract was then extracted with 1N NaOH (3×200mL). The combined 1N NaOH washes were made acidic (pH 1) by the additionof concentrated HCl, and the resulting solution was extracted withdiethyl ether (3×300 mL). The combined ether extracts were dried overanhydrous magnesium sulfate, filtered, and concentrated to afford 32.6 gof 2,2-dimethyl-3-(4-methoxyphenyl)propionic acid as an oil: GC/EI-MS,m/z (rel. int.) 208 (M⁺, 7), 121 (100), 91 (5), 77 (6).

Triethylamine (16.8 g, 166 mmol) and2,2-dimethyl-3-(4-methoxyphenyl)propionic acid (32.6 g, 157 mmol) weredissolved in 30 mL of water and enough acetone to maintain solubility at0° C. A solution of ethyl chloroformate (20.1 g, 185 mmol) in acetone(100 mL) was then added dropwise. An aqueous solution (95 mL) of sodiumazide (12.9 g, 198 mmol) was then added dropwise and the resultingreaction mixture stirred 45 minutes at room temperature. Theintermediate acyl azide was then extracted into toluene (200 mL). Theorganic extract was washed with water, dried over anhydrous magnesiumsulfate, and heated at 100° C. until the evolution of nitrogen ceased(˜45 min). The toluene was removed under vacuum and replaced with benzylalcohol. The solution was then heated at 100° C. for 16 hours. Theexcess benzyl alcohol was removed under vacuum. The resulting benzylcarbamate was dissolved in absolute ethanol (200 mL) and reduced in thepresence of palladium hydroxide (2 g) under 90 p.s.i. hydrogen for 4hours at room temperature. The reaction was filtered and concentrated toa yellow oil. Vacuum distillation afforded 13.0 g of1,1-dimethyl-2-(4-methoxyphenyl)ethylamine as a clear, colorless oil:GC/EI-MS, m/z (rel. int.) 180 (M+1, 1), 164 (5), 121 (25), 91 (5), 78(19), 58 (100).

1,2-Epoxy-3-phenoxypropane (150 mg, 1 mmol) and1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (269 mg, 1.5 mmol) were usedto prepare the free base of the title compound using the method ofExample 5, supra. The hydrochloride salt was prepared by dilution of thereaction mixture with HCl (3 mmol) and water. Reversed-phasehigh-performance liquid chromatography (RP-HPLC, 0.1%/HCl toacetonitrile) of the resulting solution yielded 35 mg of the titlecompound as a white solid: GC/EI-MS, m/z (rel. int.) 314 (M-15, 1), 209(19), 208 (100), 163 (6), 120 (19), 114 (7), 106 (6), 77 (12), 70 (9),69 (15), 58 (6).

EXAMPLE 7: Resolution of the Enantiomers (R) or(S)-N-(2-Hydroxy-3-phenoxypropyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compounds 32 and 33 ##STR7##

The enantiomers of (R) and(S)-N-(2-hydroxy-3-phenoxypropyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylaminehydrochloride (compounds 32 and 33) were obtained by chiral HPLC of thefree base through ChiralCel OD (20×2.5 cm) using a combination ofhexane-isopropanol containing 0.1% diethylamine (10 mL/min) measuringoptical density at 260 nm. GC/EI-MS of each enantiomer gave m/z (rel.int.) 330 (M+1, 1), 314 (2), 208 (100), 183 (4), 163 (5), 121 (16), 77(10), 70 (11). The hydrochloride of each enantiomer was prepared bytreatment of the free base in diethyl ether with excess 1M HCl (diethylether). Evaporation of the solvent yielded the hydrochloride product asa solid.

EXAMPLE 8: Preparation ofN-[2-Hydroxy-3-(4-chlorophenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenylethylamineHydrochloride, Compound 5 ##STR8##

Using the method of Example 6, supra, 4-chlorophenyl glycidyl ether (185mg, 1 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (269 mg, 1.5mmol) were used to prepare 272 mg of the title compound as a whitesolid: GC/EI-MS, m/z (rel. int.) 348 (M-15, 1), 244 (35), 243 (15), 242(100), 163 (9), 121 (24), 114 (7), 71 (24), 70 (26), 58 (15), 42 (7).

EXAMPLE 9: Preparation ofN-[2-Hydroxy-3-(4-t-butylphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 6 ##STR9##

Using the method of Example 5, supra, 4-t-butylphenyl glycidyl ether(206 mg, 1 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (269 mg,1.5 mmol) were used to prepare the free base of the title compound. Thehydrochloride was prepared by dilution of the reaction mixture with HCl(3 mmol) and water, which caused the product to precipitate. The mixturewas heated to effect solution and allowed to cool slowly to crystallizethe product. The crystals were collected by filtration, washed withwater/MeOH, and dried under vacuum to give 106 mg of the title compoundas a white solid: GC/EI-MS, m/z (rel. int.) 370 (M-15, 0.1), 265 (19),264 (100), 163 (8), 121 (20), 114 (9), 91 (7), 71 (20), 70 (21), 58(10), 57 (12).

EXAMPLE 10: Resolution of the Enantiomers (r) and(S)-N-[2-Hydroxy-3-(4-t-butyl-phenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compounds 20 and 21 ##STR10##

The enantiomers of (R) and(S)-N-[2-hydroxy-3-(4-t-butylphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine hydrochloride were prepared using the method of Example 7,supra. GC/EI-MS of each enantiomer gave m/z (rel. int.) 386 (M⁺, 1), 370(2), 264 (100), 163 (10), 135 (4), 121 (36), 91 (8), 70 (11). Thehydrochloride salt of each enantiomer was prepared by treatment of thecorresponding free base in diethyl ether with excess 1M HCl (diethylether). Evaporation of the solvent yielded the correspondinghydrochloride product as a solid.

EXAMPLE 11: Preparation ofN-[2-Hydroxy-3-(4-methoxyphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 7 ##STR11##

Using the method of Example 8, supra, 4-methoxyphenyl glycidyl ether(180 mg, 1 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (269 mg,1.5 mmol) were used to prepare 231 mg of the title compound as a whitesolid: GC/EI-MS, m/z (rel. int.) 344 (M-15, 0.1), 239 (17), 238 (100),163 (9), 123 (7), 120 (17), 114 (6), 77 (5), 70 (13), 70 (11), 58 (6).

EXAMPLE 12: Preparation ofN-[2-Hydroxy-3-(2-methylphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 8 ##STR12##

Using the method of Example 9, supra, 2-methylphenyl glycidyl ether (164mg, 1 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (269 mg, 1.5mmol) were used to prepare 257 mg of the title compound as a whitesolid: GC/EI-MS, m/z (rel. int.) 328 (M-15, 0.1), 223 (17), 222 (100),163 (8), 121 (23), 114 (11), 91 (13), 77 (6), 71 (19), 70 (21), 58 (11).

EXAMPLE 13: Preparation ofN-[2-Hydroxy-3-(4-(2-carboxamido)indoloxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 9 ##STR13##

Using the method of Example 6, supra, 4-glycidyloxy-2-indolecarboxamide(232 mg, 1 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (269 mg,1.5 mmol) were used to prepare 222 mg of the title compound as a whitesolid: GC/EI-MS, m/z (rel. int.) 396 (M-15, 0.1), 291 (17), 290 (100),207 (10), 158 (7), 130 (7), 121 (28), 114 (19), 71 (18), 70 (15).

EXAMPLE 14: Preparation ofN-(3-Phenoxypropyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 17 ##STR14##

To a stirred suspension of 50% KF-Celite (0.35 g, 3 mmol) in anhydrousacetonitrile (10 mL) was added1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (0.27 g, 1.5 mmol) and3-phenoxypropyl bromide (0.484 g, 2.25 mmol). The reaction mixture wasrefluxed under nitrogen for 6 hours, followed by stirring at roomtemperature for 62 hours. The mixture was filtered and the filtrate, wasevaporated. The hydrochloride was prepared by dissolving the residue inHCl/methanol. The resulting solution was concentrated and dried on alyophilizer. The residue was redissolved in dry methanol and dilutedwith diethyl ether, which caused precipitation of 210 mg of the titlecompound as a white solid: GC/EI-MS, m/z (rel. int.) 298 (M-15, 2), 193(15), 192 (100), 120 (13), 107 (5), 98 (9), 77 (8), 72 (7), 71 (8), 70(6), 41 (4).

EXAMPLE 15: Preparation ofN-[2-Hydroxy-3-(1-naphthoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 19 ##STR15##

Using the method of Example 5, supra, 1-naphthyl glycidyl ether (1:0 g,5 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (1.0 mg, 5.6mmol) were used to prepare the free base of the title compound. Silicagel chromatography of the reaction mixture using 5% methanol inchloroform afforded 1.66 g (88%) of the purified product: GC/EI-MS, m/z(rel. int.) 364 (M-15, 1), 258 (100), 183 (3), 163 (4), 144 (4), 121(23), 115 (18), 71 (19): ¹ H-NMR (C₆ D₆) δ 8.50 (1H, d, J=8.0), 7.65(1H, d, J=7.2), 7.36-7.31 (3H, m), 7.21 (1H, t, J=7.9), 6.98 (2H, d,J=8.6), 6.71 (2H, d, J=8.6), 6.62 (1H, d, J=7.7), 4.08 (2H, m), 3.93(1H, m), 3.32 (3H, s), 2.80 (1H, dd, J=11.6 and 3.7), 2.71 (1H, dd,J=11.4 and 6.4), 2.47 (2H, dd, J=13.3 and 6.2), 0.94 (3H, s), 0.92 (3H,S); ¹³ C-NMR (CDCl₃) δ 158.0, 154.3, 134.4, 131.2 (2 carbons), 129.9,127.4, 126.3, 125.8, 125.2, 121.8, 120.5, 113.3 (2 carbons), 104.8,70.4, 68.5, 55.0, 53.2, 46.4, 44.5, 26.9, 26.8. A portion of the freebase in diethyl ether was treated with excess 1M HCl (diethyl ether).The resulting solid was recrystallized from hot acetonitrile to affordthe title compound as a white solid.

EXAMPLE 16: Preparation ofN-(2-Hydroxy-3-t-butoxypropyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine.Compound 25 ##STR16##

Using the method of Example 15, supra, t-butylglycidyl ether (142 mg,1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1mmol) were used to prepare 106 mg of the title compound as a clear,colorless oil: GC/EI-MS, m/z (rel. int.) 310 (M+1. 0.3), 294 (0.5), 222(1.8), 188 (67.9), 163 (14.6), 132 (100), 121 (19.1); ¹ H-NMR (CDCl₃) δ7.09 (2H, d, J=8.6), 6.82 (2H, d, J=8.6), 3.78 (3H, s), 3.68 (1H, m),3.37 (2H, m), 2.27 (1H, dd, J=11.5 and 4.2), 2.63 (3H, m), 1.19 (9H, s),1.05 (3H, s), 1.03 (3H, s); ¹³ C-NMR (CDCl₃) δ 156.0, 131.3, 130.3,113.3, 72.9, 69.7, 64.5, 55.1, 52.9, 46.6, 44.7, 27.4, 26.9, 26.8.

EXAMPLE 17: Preparation ofN-(2-Hydroxy-3-butoxypropyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine.Compound 26 ##STR17##

Using the method of Example 15, supra, n-butyl glycidyl ether (143 μL,1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1mmol) were used to prepare 81 mg of the title compound as a clear,colorless oil: GC/EI-MS, m/z (rel. int.) 310 (M+1, 0.01), 174 (100), 163(19), 132(18), 121(31), 70(20); ¹ H-NMR (CDCl₃) δ 7.03 (2H, d, J=8.6),6.87 (2H, d, J=8.6), 3.74 (1H, m), 3.72 (3H, s), 3.40 (4H, m), 2.73 (3H,m), 2.59 (3H, m), 1.50 (2H, m), 1.30 (2H, m), 1.01 (3H, s), 0.99 (3H,s), 0.87 (3H, t, J=7.4); ¹³ C-NMR (CDCl₃) δ 157.9, 131.2, 129.9, 113.2,73.5, 71.2, 69.0, 54.9, 53.1, 46.2, 44.5, 31.5, 26.6, 26.4, 19.1, 13.8.

EXAMPLE 18: Preparation ofN-(2-Hydroxy-3-isopropoxypropyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine.Compound 27 ##STR18##

Using the method of Example 15, supra, isopropylglycidyl ether (126 μL,1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1mmol) were used to prepare 53 mg of the title compound as a clear,colorless oil; GC/EI-MS, m/z (rel. int.) 296 (M+1, 0.2), 280 (1.4), 222(1.5), 174 (100), 132 (12), 121(24); ¹ H-NMR (CDCl₃) δ 7.03 (2H, d,J=8.4), 6.77 (2H, d, J=8.4), 3.72 (3H, s), 3.70 (1H, m), 3.53 (1H, m),3.38 (2H, m), 2.80 (1H, broad s), 2.73 (2H, m), 2.58 (4H, m) 1.09 (6H,m), 1.01 (3H, s), 0.99 (3H, s); ¹³ C-NMR (CDCl₃) δ 157.9, 131.2, 129.9,113.2, 73.4, 71.2, 69.0, 54.9, 53.1, 46.2, 44.5, 31.5, 26.6, 26.4, 19.1,13.8.

EXAMPLE 19: Preparation ofN-[2-Hydroxy-3-(2-ethyl)hexanoxypropyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine.Compound 28 ##STR19##

Using the method of Example 15, supra, 2-ethylhexyl glycidyl ether (209μL, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg,1.1 mmol) were used to prepare 55 mg of the title compound as a clear,colorless oil: GC/EI-MS, m/z (rel. int.) 366 (M+1. 0.2), 350 (1.1), 244(100), 222 (2.5), 163 (8.7), 121 (15); ¹ H-NMR (CDCl₃) δ 7.06 (2H, d,J=8.5), 6.80 (2H, d, J=8.6), 3.75 (3H, s), 3.4 (2H, d, J=5.3), 3.31 (2H,d, J=6.0), 2.88 (1H, broad), 2.78 (1H dd, J=11.6 and 4.0), 2.62 (2H, m),1.46 (1H, q, J=5.7), 1.24 (6H, m), 1.03 (4H, m), 0.84 (4H, m); ¹³ C-NMR(CDCl₃) δ 158.0, 131.3, 130.0, 113.3, 74.4, 73.7, 69.0, 55.1, 53.3,46.3, 44.6, 39.5, 30.5, 29.0, 26.6, 26.4, 23.8, 23.0, 14.0, 11.0; Anal.calculated for C₂₂ H₃₉ NO₃ : C, 72.3, H, 10.8, N, 3.8. Found: C, 72.2,H, 9.9, N, 3.6.

EXAMPLE 20: Resolution of the Enantiomers (R) and(S)-N-[2-Hydroxy-3-(2-ethyl)hexanoxypropyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compounds 63 and 64 ##STR20##

The enantiomers (R) and(S)-N-[2-hydroxy-3-(2-ethyl)hexanoxypropyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylaminehydrochloride were prepared using the method of Example 7, supra.GC/EI-MS of each enantiomer gave m/z (rel. int.) 366 (M+1, 1), 350 (2),244 (100), 222 (3), 163 (12), 133 (9), 121 (21), 115 (11), 100 (4), 71(21). The hydrochloride salt of each enantiomer was prepared bytreatment of the free amine in diethyl ether with excess 1M HCl (diethylether). Evaporation of the solvent yielded the hydrochloride product asa solid.

EXAMPLE 21: Preparation ofN-(2-Hydroxy-3-allyloxypropyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine.Compound 29 ##STR21##

Using the method of Example 15, supra, allyl glycidyl ether (119 μL, 1.0mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol)were used to prepare 79 mg of the title compound as a clear, colorlessoil: GC/EI-MS, m/z (rel. int.) 294 (M+1, 0.1), 278 (0.9), 222 (1.5), 172(100), 163 (11), 121 (20); ¹ H-NMR (CDCl₃) δ 7.04 (2H, d, J=8.6), 6.79(2H, d, J=8.6), 5.85 (1H, ddd, J=22.2, 10.5 and 5.7), 5.23 (1H, dd,J=17.3 and 1.5), 5.14 (1H, dd, J=10.3 and 1.5), 3.96 (2H, d, J=5.7),3.74 (4H, m), 3.43 (2H, d, J=5.7), 2.83 (1H, broad s), 2.77 (1H, dd,J=11.7 and 4.1), 2.62 (5H, m), 1.02 (3H, s), 1.01 (3H, S); ¹³ C-NMR(CDCl₃) δ 158.0, 134.5, 131.3, 129.9, 117.0, 113.3, 72.8, 72.2, 69.0,55.0, 53.3, 46.3, 44.5, 26.6, 26.4.

EXAMPLE 22: Preparation ofN-[2-Hydroxy-3-(2-naphthoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 35 ##STR22##

Using the method of Example 4, supra, 2-naphthyl glycidyl ether (400 mg,2 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (358 mg, 2 mmol)were used to prepare the free base of the title compound: GC/EI-MS, m/z(rel. int.) 364 (M-15, 1), 258 (100), 183 (2), 163 (3), 144 (4), 127(10), 121 (22), 115 (20), 71 (11). The free base in diethyl ether wastreated with excess 1M HCl (diethyl ether). The resulting solid wasrecrystallized from hot acetonitrile to afford 496 mg of thehydrochloride product as a white solid.

EXAMPLE 23: Preparation ofN-(2-Hydroxy-3-phenylpropyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 37 ##STR23##

Using the method of Example 6, supra, 2,3-epoxypropylbenzene (1 mmol)and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (1.25 mmol) yielded 179mg of the title compound as a white solid: GC/EI-MS, m/z (rel. int.) 298(M-15, 1), 193 (16), 192 (100), 163 (7), 121 (18), 117 (12), 91 (32), 77(5), 76 (5), 70 (16), 58 (9).

EXAMPLE 24: Preparation ofN-[2-Hydroxy-3-(3-methoxyphenoxy)-propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 38 ##STR24##

Using the method of Example 6, supra, 3-methoxyphenyl glycidyl ether(1.5 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (1.9 mmol)yielded 403 mg of the title compound as a white solid: GC/EI-MS, m/z(rel. int.) 344 (M-15, 1), 239 (21), 238 (100), 163 (10), 121 (16), 114(9), 106 (3), 77 (5), 71 (7), 70 (10), 58 (4).

EXAMPLE 25: Preparation ofN-[2-Hydroxy-3-(3-fluorophenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 39 ##STR25##

A solution of 3-fluorophenol (1.8 g, 16.1 mmol) in acetone (100 mL) wastreated with potassium carbonate (6.65 g, 48.2 mmol) and refluxed undernitrogen for 15 minutes. Epibromohydrin (4.4 g, 32.1 mmol) was thenadded by syringe, and the mixture was refluxed 3 hours. The mixture wascooled and filtered, and the filtrate evaporated to dryness. The residuewas partitioned between ether/water, and the layers separated. The etherlayer was washed with saturated NaCl, dried over sodium sulfate andevaporated. The resulting oil was distilled under vacuum to give 1.2 gof 3-fluorophenyl glycidyl ether.

Using the method of Example 6, supra, 3-fluorophenyl glycidyl ether (1.5mmol) and 1,1-dimethyl-2-(4-5 methoxyphenyl)ethylamine (1.9 mmol)yielded 398 mg of the title compound as a white solid: GC/EI-MS, m/z(rel. int.) 332 (M-15, 1), 227 (22), 226 (100), 163 (7), 151 (6), 120(22), 114 (6), 94 (7), 71 (11), 70 (16), 57 (8).

EXAMPLE 26: Preparation ofN-[2-Hydroxy-3-(2-chlorophenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 40 ##STR26##

Using the method of Example 25, supra, 2-chlorophenyl glycidyl ether(1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (1.25 mmol)yielded 279 mg of the title compound as a white solid: GC/EI-MS, m/z(rel. int.) 348 (M-15, 5), 245 (21), 244 (100), 242 (100), 163 (29), 121(82), 114 (24), 77 (21), 71 (44), 70 (56), 58 (24).

EXAMPLE 27: Preparation ofN-[2-Hydroxy-3-(2-fluorophenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 41 ##STR27##

Using the method of Example 25, supra, 2-fluorophenyl glycidyl ether(1.5 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (1.9 mmol)yielded 385 mg of the title compound as a white solid: GC/EI-MS, m/z(rel. int.) 332 (M-15, 2), 227 (20), 226 (100), 163 (4), 125 (3), 121(15), 78 (4), 77 (4), 71 (7), 70 (9), 58 (3).

EXAMPLE 28: Preparation ofN-[2-Hydroxy-3-(3-chlorophenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine Hydrochloride, Compound 43 ##STR28##

Using the method of Example 25, supra, 3-chlorophenyl glycidyl ether(1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (1.25 mmol)yielded 168 mg of the title compound as a white solid: GC/EI-MS, m/z(rel. int.) 348 (M-15, 0.9), 245 (7), 244 (35), 243 (25), 242 (100), 163(7), 121 (22), 71 (11), 70 (16).

EXAMPLE 29: Preparation ofN-[2-Hydroxy-3-(4-fluorophenoxy)-propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine Hydrochloride, Compound 44 ##STR29##

Using the method of Example 25, supra, 4-fluorophenyl glycidyl ether(1.5 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (1.9 mmol)yielded 398 mg of the title compound as a white solid: GC/EI-MS, m/z(rel. int.) 332 (M-15, 1), 227 (20), 226 (100), 163 (5), 125 (4), 121(15), 114 (3), 95 (4), 71 (8), 70 (10), 58 (5).

EXAMPLE 30: Preparation ofN-[2-Hydroxy-3-(3-methylphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine Hydrochloride, Compound 45 ##STR30##

Using the method of Example 25, supra, 3-methylphenyl glycidyl ether(2.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (2.5 mmol)yielded 400 mg of the title compound as a white solid: GC/EI-MS, m/z(rel. int.) 328 (M-15,1), 223 (16), 222 (100), 163 (5), 147 (5), 121(18), 114 (6), 91 (8), 76 (4), 71 (6), 70 (11).

EXAMPLE 31: Preparation ofN-[2-Hydroxy-3-(3-trifluoromethylphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 46 ##STR31##

Using the method of Example 25, supra, 3-trifluoromethylphenyl glycidylether (2.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (2.5mmol) yielded 600 mg of the title compound as a white solid: GC/EI-MS,m/z (rel. int.) 382 (M-15, 1), 277 (16), 276 (100), 163 (7), 126 (4),121 (18), 114 (5), 96 (6), 71 (8), 70 (15), 57 (4).

EXAMPLE 32: Preparation ofN-[2-Hydroxy-3-(2-trifluoromethylphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 47 ##STR32##

Using the method of Example 25, supra, 2-trifluoromethylphenyl glycidylether (2.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (2.5mmol) yielded 690 mg of the title compound as a white solid: GC/EI-MS,m/z (rel. int.) 382 (M-15, 1), 277 (16), 276 (100), 163 (10), 121 (22),114 (8), 96 (11), 71 (17), 70 (33), 58 (9), 42 (6).

EXAMPLE 33: Preparation ofN-[2-Hydroxy-3-(2-t-butylphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 48 ##STR33##

Using the method of Example 25, supra, 2-t-butylphenyl glycidyl ether(2.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (2.5 mmol)yielded 540 mg of the title compound as a white solid: GC/EI-MS, m/z(rel. int.) 370 (M-15, 1), 265 (19), 264 (100), 163 (5), 121 (17), 114(6), 91 (8), 77 (3), 71 (9), 70 (8), 58 (3).

EXAMPLE 34: PreparationN-[2-Hydroxy-3-(2-methoxyphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 49 ##STR34##

Using the method of Example 25, supra, 2-methoxyphenyl glycidyl ether(2.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (2.5 mmol)yielded 60 mg of the title compound as a white solid: GC/EI-MS, m/z(rel. int.) 344 (M-15, 0.1), 239 (15), 238 (100), 163 (9), 122 (7), 121(20), 114 (13), 77 (10), 71 (19), 70 (21), 58 (7).

EXAMPLE 35: Preparation ofN-[2-Hydroxy-3-(3-t-butylphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 50 ##STR35##

Using the method of Example 25, supra, 3-t-butylphenyl glycidyl ether(2.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (2.5 mmol)yielded 400 mg of the title compound as a white solid: GC/EI-MS, m/z(rel. int.) 370 (M-15, 1), 265 (19), 264 (100), 163 (5), 121 (15), 114(5), 110 (3), 91 (4), 71 (6), 70 (9), 57 (3).

EXAMPLE 36: Preparation ofN-[2-Hydroxy-3-(4-trifluoromethylphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 51 ##STR36##

Using the method of Example 25, supra, 4-trifluoromethylphenyl glycidylether (1.43 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (1.8mmol) yielded 270 mg of the title compound as a white solid: GC/EI-MS,m/z (rel. int.) 382 (M-15, 3), 277 (35), 276 (100), 175 (8), 163 (8),145 (16), 121 (34), 78 (9), 71 (15), 70 (19), 58 (8).

EXAMPLE 37: Preparation ofN-(2-Hydroxy-3-phenoxypropyl)-1,1-dimethyl-2-phenylethylamineHydrochloride, Compound 56 ##STR37##

Using the method of Example 5, supra, 1,2-epoxy-3-phenoxypropane (600mg, 4 mmol) and 1,1-dimethyl-2-phenylethylamine (596 mg, 4 mmol) yieldedthe title compound: GC/EI-MS, m/z (rel. int.) 284 (M+1, 1), 208 (100),162 (1), 133 (7), 91 (27), 77 (15), 70 (22). The free base in diethylether was treated with excess 1M HCl (diethyl ether). The resultingsolid was recrystallized from hot acetonitrile to afford 596 mg of thehydrochloride product as a white solid.

EXAMPLE 38: Preparation ofN-(2-Methoxy-3-phenoxypropyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 59 ##STR38##

Allyl phenyl ether (1.34 g, 10 mmol) and N-bromosuccinimide (1.78 g, 10mmol) were dissolved in 50 mL of methanol and stirred at roomtemperature for two days. The product, a 1:1 mixture of2-bromo-1-methoxy-3-phenoxypropane and1-bromo-2-methoxy-3-phenoxypropane, was isolated by evaporating themethanol and dissolving the residue in heptane/ether/water. The organiclayer was washed first with water, then brine, dried over sodiumsulfate, and evaporated to dryness. The crude mixture (1.47 g, 6 mmol)was dissolved in 6 mL of acetonitrile, to which was added 50 KF-Celite(0.7 g, 12 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (0.54 g,3 mmole). The mixture was refluxed under nitrogen for 48 hours, and thencooled and filtered. The filtrate was evaporated to dryness, and theresidue was taken up in water and ether. The ether layer was dried oversodium sulfate and concentrated to dryness. The residue was dissolved in10 mL of diethyl ether and precipitated as the HCl salt by the additionof 10 mL of 1M HCl (diethyl ether). The collected solid was purified byRP-HPLC to yield 330 mg of the title compound as a white solid:GC/EI-MS, m/z (rel. int.) 328 (M-15, 5), 223 (43), 222 (100), 163 (9),133 (13), 121 (42), 107 (13), 78 (11), 77 (23), 71 (12), 70 (32).

EXAMPLE 39: Preparation ofN-(2-Hydroxy-3-octanoxypropyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine.Compound 65 ##STR39##

Using the method of Example 5, supra, 1-octyl glycidyl ether (187 mg,1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1mmol) were used to prepare 105 mg of the title compound as a clear,colorless oil: GC/EI-MS, m/z (rel. int.) 366 (M+1, 0.08), 350 (0.08),244 (100), 222 (5.8), 163 (12), 121 (18): ¹ H-NMR (CDCl₃) δ 7.08 (2H, d,J=8.6), 6.82 (2H, d, J=8.6), 3.79 (1H, m), 3.77 (3H, s), 3.45 (4H, m),2.92 (1H, broad s), 2.79 (1H, dd, J=11.6 and 4.1), 2.65 (2H, m), 2.55(2H, m), 1.27 (8H, m), 1.06 (3H, s), 1.04 (3H, s), 0.88 (3H, t, J=6.7);¹³ C-NMR (CDCl₃) δ 158.0, 131.2, 129.9, 113.2, 73.4, 71.6, 68.9, 55.0,53.3, 46.2, 44.6, 31.7, 29.5, 29.3, 29.1, 26.5, 26.4, 26.0, 22.5, 14.0;FT-IR (film) cm⁻¹ 3409 (broad), 1611, 1512, 1245, 1120.

EXAMPLE 40: Preparation ofN-(2-Hydroxy-3-hexanoxypropyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine.Compound 66 ##STR40##

Using the method of Example 5, supra, 1-hexyl glycidyl ether (175 mg,1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1mmol) were used to prepare 95 mg of the title compound as a clear,colorless oil: GC/EI-MS, m/z (rel. int.) 216 (M-121), 163 (11), 121(22), 114 (14); ¹ H-NMR (CDCl₃) δ 7.05 (2H, d, J=8.7), 6.79 (2H, d,J=8.7), 3.77 (1H, m), 3.75 (3H, s), 3.41 (4H, m), 2.97 (2H, broad), 2.79(1H, dd, J=11.7 and 4.1), 2.64 (3H, m), 1.52 (2H, m), 1.26 (6H, m), 1.04(3H, s), 1.03 (3H, s), 0.85 (3H, t, J=6.7); ¹³ C-NMR (CDCl₃) δ 158.1,131.3, 129.9, 113.4, 73.4, 71.7, 68.9, 55.1, 53.6, 46.3, 44.6, 31.6,29.5, 26.5, 26.4, 25.7, 22.6, 14.0; FT-IR, cm⁻¹ 3405 (broad), 1611,1512, 1245, 1116, 824.

EXAMPLE 41: Preparation ofN-(2-Hydroxy-3-decanoxypropyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine,Compound 67 ##STR41##

Using the method of Example 5, supra, 1-decyl glycidyl ether (235 mg,1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1mmol) were used to prepare 175 mg of the title compound as a clear,colorless oil: GC/EI-MS, m/z (rel. int.) 394 (M+1, 1), 378 (6), 273(97), 272 (100), 222 (9), 163 (37), 121 (61); ¹ H-NMR (CDCl₃) δ 7.49(2H, d, J=8.5), 6.82 (2H, d, J=8.5 Hz), 3.78 (3H, s), 3.75 (1H, m), 3.45(4H, m), 2.80 (1H, dd, J=11.7 and 4.0), 2.77 (1H, broad s), 2.64 (4H,m), 1.56 (2H, m), 1.26 (16 H, m), 1.06 (3H, s), 1.05 (3H, s), 0.88 (3H,t, J=6.1); ¹³ C-NMR (CDCl₃) δ 158.1, 131.3, 130.0, 113.4, 73.5, 71.7,69.1, 55.1, 53.3, 46.4, 44.6, 31.8, 29.6, 29.5, 29.4, 29.3, 26.7, 26.6,26.1, 22.6, 14.1; FT-IR (film) cm⁻¹ 3115 (broad s), 1612, 1512, 1245,1121, 824.

EXAMPLE 42: Preparation ofN-(2-Hydroxy-3-thiophenylpropyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine.Compound 68 ##STR42##

Using the method of Example 25, supra, phenyl glycidyl sulfide (3.9mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (4.9 mmol) yielded194 mg of the title compound as a white solid: GC/EI-MS, m/z (rel. int.)330 (M-15, 4), 226 (21), 225 (58), 224 (100), 163 (25), 149 (25), 123(100), 121 (75), 77 (18), 71 (22), 70 (26).

EXAMPLE 43: Preparation ofN-(2-Hydroxydecanyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine.Compound 69 ##STR43##

Using the method of Example 5, supra, 1,2-epoxydecane (204 mg, 1.0 mmol)and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) wereused to prepare 73 mg of the title compound as a clear, colorless oil:GC/EI-MS, m/z (rel. int.) 214 (M-121, 100), 196 (27.8), 163 (10), 121(2.2); ¹ H-NMR (CDCl₃) δ 7.08 (2H, d, J=8.6), 6.83 (2H, d, J=8.6), 3.79(3H, s), 3.53 (1H, m), 2.79 (1H, dd, J=11.7 and 2.9), 2.67 (2H, s), 2.42(1H, dd, J=12.6 and 9.6), 1.26 (18 H, m), 1.08 (3H, s), 0.88 (3H, t,J=6.6); ¹³ C-NMR (CDCl₃) δ 158.2, 131.4, 129.8, 113.5, 77.2, 69.8, 55.2,53.8, 47.8, 46.5, 35.1, 31.9, 29.8, 29.7, 29.6, 29.3, 26.6, 26.4, 25.7,22.7, 14.1; FT-IR (film) cm⁻¹ 3399 (broad s), 1612, 1512, 1246, 1039,823.

EXAMPLE 44: Preparation ofN-(2-Hydroxydodecanyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine.Compound 70 ##STR44##

Using the method of Example 5, supra, 1,2-epoxydodecane (240 μL, 1.0mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol)were used to prepare 68 mg of the title compound as a clear, colorlessoil: GC/EI-MS, m/z (rel. int.) 363 (M+1, 0.2), 348 (2), 242 (100), 224(8), 163 (7), 121 (20); ¹ H-NMR (CDCl₃) δ 7.08 (2H, d, J=8.4), 6.83 (2H,d, J=8.4), 3.79 (3H, s), 3.50 (1H, m), 2.78 (1H, dd, J=11.8 and 3.1),2.66 (2H, s), 2.41 (1H, dd, J=11.5 and 9.3), 1.26 (18 H, m), 1.07 (6H,s), 0.88 (3H, t, J=6.5); ¹³ C-NMR (CDCl₃) δ 158.2, 131.4, 129.9, 113.4,76.9, 70.0, 55.2, 53.6, 47.8, 46.6, 35.1, 31.9, 29.7, 29.6, 29.3, 26.7,26.5, 25.7, 22.7, 14.1; FT-IR (film) cm⁻¹ 3386, 1612, 1512, 1246, 1039,824.

EXAMPLE 45: Preparation ofN-(2-Hydroxydec-9-enyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine.Compound 71 ##STR45##

Using the method of Example 5, supra, 1,2-epoxy-9-decene (202 mg, 1.0mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol)were used to prepare 80 mg of the title compound as a clear, colorlessoil: GC/EI-MS, m/z (rel. int.) 334 (M+1, 0.02), 318 (0.7), 212 (100),194 (13), 163 (11), 121 (23); ¹ H-NMR (CDCl₃) δ 7.06 (2H, d, J=8.6),6.80 (2H, d, J=8.6), 5.79 (1H, dddd, J=23.1, 10.2, 6.6 and 6.6), 4.95(2H, m), 3.77 (3H, s), 3.52 (1H, m), 2.76 (1H, dd, J=11.7 and 3.0), 2.64(1H, s), 2.39 (1H, dd, J=11.6 and 9.4), 2.03 (2H, m), 1.33 (10H, m),1.05 (6H, s): ¹³ C-NMR (CDCl₃) δ 158.1, 139.1, 131.4, 129.8, 114.1,113.4, 69.8, 55.2, 53.7, 47.8, 46.5, 35.1, 33.8, 29.6, 29.0, 28.8, 26.6,26.4, 25.7; FT-IR (film) cm-¹ 3387 (broad, s), 1612, 1512, 1246, 1038,910, 760.

EXAMPLE 46: Preparation ofN-(3-Dodecanoxy-2-hydroxypropyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine,Compound 72 ##STR46##

Using the method of Example 5, supra, dodecyl glycidyl ether (242 mg,1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1mmol) were used to prepare 121 mg of the title compound as a clear,colorless oil: GC/EI-MS, m/z (rel. int.) 422 (M+1, 1), 406 (4), 300(100), 222 (11), 163 (23), 121 (34); ¹ H-NMR (CDCl₃) δ 7.09 (2H, d,J=8.6), 6.83 (2H, d, J=8.6), 3.79 (3H, s), 3.76 (1H, m), 3.45 (4H, m),2.81 (1H, dd, J=7.6 and 4.0), 2.65 (4H, m), 1.53 (2H, m), 1.26 (20H, m),1.06 (3H, s), 1.05 (3H, s), 0.88 (3H, t, J=6.4); ¹³ C-NMR (CDCl₃) δ158.1, 131.3, 130.0, 113.4, 73.5, 71.7, 69.0, 55.1, 53.4, 46.4, 44.6,31.9, 29.6, 29.4, 29.3, 26.7, 26.6, 26.1, 22.7, 14.1; FT-IR (film) cm⁻¹3415 (broad, s), 1612, 1512, 1246, 1121, 825.

EXAMPLE 47: Preparation ofN-[2-Hydroxy-3-(1-adamantylmethoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine Hydrochloride, Compound 74 ##STR47##

Using the method of Example 9, supra,1,2-epoxy-3-(1-adamantylmethoxy)propane (410 mg, 1.8 mmol) and1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (403 mg, 2.25 mmol) were usedto prepare 625 mg of the title compound as a white solid: GC/EI-MS, m/z(rel. int.) 386 (M-15, 5), 281 (97), 280 (100), 163 (26), 149 (77), 135(23), 121 (63), 107 (18), 93 (29), 79 (20), 71 (26).

EXAMPLE 48: Preparation ofN-(2-Hydroxy-3-cyclohexylmethoxypropyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine Hydrochloride, Compound 75 ##STR48##

Using the method of Example 6, supra,1,2-epoxy-3-cyclohexylmethoxypropane (212 mg, 1.2 mmol) and1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (279 mg, 1.6 mmol) were usedto prepare 200 mg of the title compound as a white solid: GC/EI-MS, m/z(rel. int.) 334 (M-15,0.1), 229 (15), 228 (100), 163 (9), 132 (5), 121(16), 114 (9), 97 (7), 71 (8), 70 (9), 55 (16).

EXAMPLE 49: Preparation ofN-(2-Hydroxy-4-phenylbutyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 79 ##STR49##

A solution of m-chloroperbenzoic acid (43.5 g, 151 mmol) in chloroform(250 ml) was treated with 4-phenyl-1-butene (20 g, 151 mmol). Thereaction was stirred for 1 hour at room temperature and washed withsodium bicarbonate, sodium sulfite, and saturated sodium chloride. Thesolution was dried over sodium sulfate and evaporated to dryness toafford 3,4-epoxybutylbenzene (100%).

Using the method of Example 6, supra, 3,4-epoxybutylbenzene (1.4 mmol)and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (1.7 mmol) were used toprepare 235 mg of the title compound as a white solid: GC/EI-MS, m/z(rel. int.) 312 (M-15, 0.1), 207 (16), 206 (100), 163 (7), 131 (28), 121(19), 91 (28), 77 (7), 71 (7), 70 (10), 58 (10).

EXAMPLE 50: Preparation of N-(2-Hydroxy-3-phenoxypropyl)-1,1-dimethyl-3-(4-methoxyphenyl)propylamine Hydrochloride, Compound 90 ##STR50##

4-Methoxycinnamonitrile was hydrogenated in ethanol with palladiumhydroxide on carbon to give 3-(4-methoxyphenyl)propionitrile. A mixtureof anhydrous cerium (III) chloride (1.99 g, 8.1 mmol) in dry THF (12 mL)was stirred for 3 hours at room temperature, cooled to -78° C., andtreated with MeLi (5.8 mL, 8.1 mmol). After stirring for 1 hour at -78°C. the reaction mixture was treated with3-(4-methoxyphenyl)propionitrile (0.45 g, 2.8 mmol). The reactionmixture was stirred for 5 hours at -78° C. and then quenched withammonium hydroxide. After warming to room temperature, the mixture wasfiltered, and the filtrate diluted with water and extracted with diethylether. The diethyl ether layer was dried over sodium sulfate andevaporated. The crude oil was purified by normal-phase chromatography togive 150 mg of 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine as a lightyellow oil.

Using the method of Example 6, supra, 1,2-epoxy-3-phenoxypropane (0.62mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (0.78 mmol) wereused to prepare 105 mg of the title compound as a white solid: GC/EI-MS,m/z (rel. int.) 343 (M⁺, 4), 209 (14), 208 (99), 161 (13), 122 (9), 121(100), 77 (17), 72 (25), 71 (12), 70 (18), 58 (13).

EXAMPLE 51: Preparation ofN-[2-Hydroxy-3-(1-adamantanoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine. Compound 96 ##STR51##

Using the method of Example 16, supra, 1-adamantyl glycidyl ether (350mg, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg,1.1 mmol) were used to prepare 207 mg of the title compound as a clear,colorless oil: GC/EI-MS, m/z (rel. int.) 338 (M+1, 0.1), 372 (0.3), 266(65), 163 (1), 135 (100), 121 (16); ¹ H-NMR (CDCl₃) δ 7.02 (2H, d,J=8.3), 6.74 (2H, d, J=8.6), 3.70 (3H, s), 3.64 (1H, m), 3.38 (4H, m),2.71 (1H, dd, J=11.5 and 4.0), 2.57 (3H, m), 2.06 (3H, broad s), 1.64(6H, broad s), 1.53 (6H, m), 1.13 (4H, apparent t, J=6.9), 0.98 (3H, s),0.97 (3H, s); ¹³ C-NMR (CDCl₃) δ 157.8, 131.2, 130.0, 113.1, 77.8, 70.5,69.4, 54.9, 52.8, 46.3, 44.6, 32.0, 26.7, 26.6, 25.6, 23.9.

EXAMPLE 52: Preparation ofN-(2-Hydroxy-3-phenoxypropyl)-1,1-dimethyl-2-(4-methylphenyl)ethylamineHydrochloride, Compound 98 ##STR52##

A solution of 2,4,6-triphenylpyrylium tetrafluoroborate (2.97 g, 7.5mmol) in ethanol (15 mL) was treated with 4-methylbenzylamine (1 g, 8.25mmol). The reaction was stirred overnight at room temperature anddiluted with diethyl ether to precipitate the product. The product wasrecrystallized from ethanol/diethyl ether to give 3.15 g ofN-(4-methylbenzyl)-2,4,6-triphenylpyridinium tetrafluoroborate as a tansolid.

Sodium hydride (0.92 g, 60% oil dispersion, 22.9 mmol) was added tomethanol (10 mL) at 0° C., followed by the addition of 2-nitropropane(2.04 g, 22.9 mmol). The reaction mixture was stirred for 30 minutes atroom temperature and the methanol was evaporated at reduced pressure. Asolution of the N-(4-methylbenzyl)-2,4,6-triphenylpyridiniumtetrafluoroborate (3.15 g, 7.6 mmol) in DMSO (25 mL) was then added tothe dry sodium salt of 2-nitropropane. The mixture was stirred at 60° C.overnight under nitrogen. The reaction was diluted with water, and theproduct extracted into diethyl ether. The ether layer was washed withsaturated NaCl and dried over sodium sulfate. The ether solution wastreated with Amberlyst 15 ion-exchange resin to absorb the2,4,6-triphenylpyridine. The resin was filtered and the filtrateevaporated to yield 1.3 g of pure1-(4-methylphenyl)-2-methyl-2-nitropropane.

The 1-(4-methylphenyl)-2-methyl-2-nitropropane (1.3 g) was hydrogenatedfor 5 hours at 65 p.s.i. hydrogen in ethanol (30 mL) using 1.4 g ofRaney nickel as catalyst. Removal of the catalyst by filtration andevaporation of the solvent yielded 1.15 g of1,1-dimethyl-2-(4-methoxyphenyl)ethylamine as a clear oil.

Using the method of Example 6, supra, 1,2-epoxy-3-phenoxypropane (1.3mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (0.6 mmol) wereused to prepare 85 mg of the title compound as a white solid: GC/EI-MS,ml/z (rel. int.) 298 (M-15, 7), 209 (47), 208 (100), 114 (14), 107 (13),105 (46), 79 (12), 77 (28), 71 (18), 70 (31), 58 (13).

EXAMPLE 53: Preparation ofN-(2-Hydroxy-3-phenoxypropyl)-1,1-dimethyl-2-(3-methoxyphenyl)ethylamineHydrochloride, Compound 99 ##STR53##

Using the method of Example 6, supra, 1,2-epoxy-3-phenoxypropane (200mg, 1.3 mmol) and 1,1-dimethyl-2-(3-methoxyphenyl)ethylamine (263 mg,1.5 mmol) were used to prepare 340 mg of the title compound as a whitesolid: GC/EI-MS, m/z (rel. int.) 209 (14), 208 (100), 206 (6), 121 (11),114 (5), 107 (5), 91 (6), 77 (12), 71 (8), 70 (16).

EXAMPLE 54: Preparation ofN-(2-Hydroxy-2-methyl-3-phenoxypropyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 101 ##STR54##

To a solution of 3-chloroperoxybenzoic acid (70% pure, 4.2 g, 17 mmol)in 40 mL of chloroform was added methallyl phenyl ether (2.5 g, 16.87mmol). The mixture was stirred at room temperature for 5 hours thenworked up by pouring into ether and sodium bicarbonate. The organicphase was washed with sodium bisulfite, sodium bicarbonate, and sodiumchloride, dried over anhydrous sodium sulfate and evaporated to give 2.3g of 1,2-epoxy-2-methyl-3-phenoxypropane.

Using the method of Example 6, supra,1,2-epoxy-2-methyl-3-phenoxypropane (0.092 g, 0.56 mmol) and1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (0.10 g, 0.56 mmol) were usedto prepare 120 mg of the title compound as a white solid: GC/EI-MS, m/z,(rel. int.) 328 (M-15,1), 223 (15), 222 (100), 163 (13), 147 (13), 121(21), 107 (11), 91 (9), 77 (13) 71 (12), 70 (49).

EXAMPLE 55: Preparation ofN-(2-Hydroxy-3-phenoxypropyl)-1,1-dimethyl-2-(4-chlorophenyl)ethylamineHydrochloride, Compound 103 ##STR55##

Using the method of Example 6, supra, 1,2-epoxy-3-phenoxypropane (950mg, 6.3 mmol) and 1,1-dimethyl-2-(4-chlorophenyl)ethylamine (1.45 g, 7.9mmol) were used to prepare 150 mg of the title compound as a whitesolid: GC/EI-MS, m/z (rel. int.) 318 (M-15, 7), 209 (47), 208 (100), 127(11), 125 (33), 114 (13), 107 (12), 77 (23), 71 (16), 70 (29), 58 (13).

EXAMPLE 56: Preparation ofN-(2-Hydroxy-3-phenoxypropyl)-1,1-dimethyl-2-(3-chlorophenyl)ethylamineHydrochloride, Compound 104 ##STR56##

Using the method of Example 6, supra, 1,2-epoxy-3-phenoxypropane (1.3 g,8.8 mmol) and 1,1-dimethyl-2-(4-chlorophenyl)ethylamine (2.0 g, 11 mmol)were used to prepare 338 mg of the title compound as a white solid:GC/EI-MS, m/z (rel. int.) 318 (M-15, 1), 209 (14), 208 (100), 133 (4),125 (12), 114 (6), 107 (6), 77 (10), 71 (8), 70 (15), 58 (5).

EXAMPLE 57: Resolution of the Enantiomers of (R)- and S)-N-[2-Hydroxy-3-(1-naphthoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compounds 105 and 106 ##STR57##

The free base (1.5 g) of compound 19 was chromatographed throughChiralCel OD (20×2.5 cm) using ethanol-hexane (1:4, plus 0.1%diethylamine) at 10 mL/min (270 nm). Chromatography of each enantiomerthrough Vydac C-18 (5×25 cm) using a gradient of 0.1% HCl toacetonitrile (50 mL/min., 264 nm) afforded the hydrochloride salt ofcompound 105 (464 mg) [α]_(D) ²⁶ =15.3° (c=0.928, CHCl₃), m.p. 113-115°C. and compound 106 (463 mg) [α]_(D) ²⁶ --13.8° (c=0.926, CHCl₃).

EXAMPLE 58: Preparation ofN-[2-Hydroxy-3-(4-methoxy-(1-naphthoxy))proyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 107 ##STR58##

Using the method of Example 5, supra,1,2-epoxy-3-[4-methoxy-(1-naphthoxy)]propane (462 mg, 2 mmol) and1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (120 mg, 0.67 mmol) yielded,after preparative TLC and RP-HPLC, 116 mg of the title compound as awhite solid: GC/EI-MS, m/z (rel. int.) 394 (M-15,2), 288 (100), 731(11), 121 (15), 71 (22).

EXAMPLE 59: Preparation ofN-[2-Hydroxy-3-(4-chloro-(1-naphthoxy))propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 108 ##STR59##

Using the method of Example 5, supra,1,2-epoxy-3-[4-chloro-(1-naphthoxy)]propane (469 mg, 2 mmol) and1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (120 mg, 0.67 mmol) yielded,after preparative TLC and RP-HPLC, 131 mg of the title compound as awhite solid: GC/EI-MS, m/z (rel. int.) 414 (M⁺, 0.5), 398 (1), 292(100), 121 (33), 71 (43).

EXAMPLE 60: Preparation of(R)-N-[2-Hydroxy-3-(3-chloro-2-cyanophenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)-ethylamineHydrochloride, Compound 109 ##STR60##

To a solution of 18-crown-6 (3.96 g, 15 mmol) in 30 mL of acetonitrilewere added dry potassium acetate (1.47 g, 15 mmol) and2-chloro-6-fluorobenzonitrile (1.56 g, 10 mmol). The reaction wasrefluxed under nitrogen for 25 hours, then cooled to room temperature.Sodium hydroxide (2 mL of a 10M solution, 20 mmol) and water (5 mL) wereadded, and the reaction stirred at room temperature for two hours. Theacetonitrile was removed on a rotary evaporator, and the residue wastaken up in ether and water. The basic aqueous layer was washed threetimes with ether. The aqueous layer was then made acidic with HCl, andthe product extracted into ether. The ether layer was dried overanhydrous sodium sulfate, filtered, and concentrated. The resultingsolid was crystallized from water/methanol to yield 1.11 g of3-chloro-2-cyanophenol.

3-Chloro-2-cyanophenol (0.55 g, 3.58 mmol) was dissolved in 10 mL ofdimethylformamide, and the solution cooled to 0° C. Sodium hydride(0.158 g, 3.94 mmol 60% in oil), washed with hexane anddimethylformamide, was added to cooled solution over a period of oneminute. After stirring for 10 minutes at room temperature,(2R)-(-)-glycidyl 3-nitrobenzenesulfonate was added and stirred 16hours. The reaction was poured into ether and dilute sodium hydroxide.The ether layer was separated and the aqueous layer extracted once morewith ether. The combined ether extracts were washed with water andsaturated brine, dried over anhydrous sodium sulfate, filtered, andconcentrated to give 0.7 g of (R)-3-chloro-2-cyanophenyl glycidyl ether.

Using the method of Example 6, supra, (R)-3-chloro-2-cyanophenylglycidyl ether (0.7 g, 3.34 mmol) and1,1-dimethyl-(4-methoxyphenyl)ethylamine (0.72 g, 4.0 mmol) were used toprepare 570 mg of the title compound as a white solid: ¹ H-NMR (CDCl₃)9.65 (1H, br s), 8.2 (1H, br s), 7.4 (1H, t), 7.15 (2H, d), 7.03 (1H,d), 6.95 (1H, d), 6.8 (2H, d), 4.8 (1H, m), 4.3 (2H, d), 3.75 (3H, s),3.4 (2H, m), 3.13 (2H, dd), 1.44 (3H, s), 1.40 (3H, s); ¹³ C-NMR 161.9,159.4, 138.2, 135.1, 132.4, 126.8, 122.8, 114.4, 114.2, 111.6, 104.0,71.8, 66.0, 61.9, 55.8, 45.4, 43.9, 23.5, 23.3.

EXAMPLE 61: Preparation ofN-(2-Hydroxy-3-phenoxypropyl)-1,1-dimethyl-2-(4-ethylphenyl)ethylamineHydrochloride, Compound 110 ##STR61##

Using the method of Example 52, supra, 4-ethylbenzylamine (4.0 g, 29.6mmol) was used to prepare 3.6 g of1,1-dimethyl-2-(4-ethylphenyl)ethylamine. Using the method of Example 6,supra, 1,2-epoxy-3-phenoxypropane (0.43 g, 2.9 mmol) and1,1-dimethyl-2-(4-ethylphenyl)ethylamine (0.5 g, 2.8 mmol) were used toprepare 600 mg of the title compound as a white solid: GC/EI-MS, m/z,(rel. int.) 313 (M-15,0.1), 209 (23), 208 (100), 133 (5), 119 (12), 114(6), 107 (5), 104 (7), 91 (6), 77 (10), 71 (8), 70 (12).

EXAMPLE 62: Preparation ofN-(2-Hydroxy-3-phenoxypropyl)-1,1-dimethyl-2-(4-trifluoromethoxyphenyl)ethylamine Hydrochloride, Compound 111 ##STR62##

Using the method of Example 52, supra, 4-trifluoromethoxybenzylamine(2.0 g, 10.5 mmol) was used to prepare 2.2 g of1,1-dimethyl-2-(4-trifluoromethoxyphenyl)ethylamine.

Using the method of Example 6, supra, 1,2-epoxy-3-phenoxypropane (0.12g, 0.8 mmol) and 1,1-dimethyl-2-(4-trifluoromethoxyphenyl)ethylamine(0.175 g, 0.8 mmol) were used to prepare 15 mg of the title compound asa white solid: GC/EI-MS, m/z, (rel. int.) 368 (M-15,2), 209 (39), 208(100), 175 (20), 133 (5), 114 (5), 107 (6), 77 (11), 71 (7), 70 (12), 58(5).

EXAMPLE 63: Preparation ofN-(2-Hydroxy-3-phenoxypropyl)-1,1-dimethyl-2-(4-isopropylphenyl)ethylamineHydrochloride, Compound 112 ##STR63##

Using the method of Example 52, supra, 4-isopropylbenzylamine (4.89 g,32.8 mmol) was used to prepare 4.1 g of1,1-dimethyl-2-(4-isopropylphenyl)ethylamine. Using the method ofExample 6, supra, 1,2-epoxy-3-phenoxypropane (0.173 g, 1.15 mmol) and1,1-dimethyl-2-(4-isopropylphenyl)ethylamine (0.275 g, 1.44 mmol) wereused to prepare 89 mg of the title compound as a white solid: GC/EI-MS,m/Z, (rel. int.) 326 (M-15,1), 209 (14), 208 (100), 133 (9), 117 (5),114 (5), 105 (5), 91 (6), 77 (8), 71 (8), 70 (13), 58 (5).

EXAMPLE 64: Preparation ofN-(2-Hydroxy-3-phenoxypropyl)-1-ethyl-1-methyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 113 ##STR64##

4-Hydroxybenzyl alcohol (0.35 g, 2.82 mmol) and tetrabutylammoniumfluoride (0.147 g, 0.56 mmol) were dissolved in 3 mL of 2-nitrobutaneand heated to 130-145° C. under nitrogen for 20 hours. The reactionmixture was cooled and partitioned between water and ether. The etherlayer was separated, washed with saturated brine, dried over anhydroussodium sulfate, and concentrated. The crude material was purified bypreparative TLC using ethyl acetate/hexane as the elutant. The yield of1-ethyl-1-methyl-2-(4-hydroxyphenyl)nitroethane was 0.21 grams.

To a suspension of 40% (wt/wt) potassium fluoride on alumina (0.73 g, 5mmol) in 3 mL of acetonitrile were added1-ethyl-1-methyl-2-(4-hydroxyphenyl)nitroethane (0.21 g, 1.0 mmol) andiodomethane (0.21 g, 1.5 mmol). The reaction was stirred at roomtemperature for 4 days and then filtered and rinsed with acetonitrile.The acetonitrile was removed on a rotary evaporator, and the residue waspartitioned between ether and water. The ether layer was separated,washed with sodium bisulfite, sodium carbonate, and saturated brine,then 10 dried over anhydrous sodium sulfate and concentrated. The yieldof 1-ethyl-1-methyl-2-(4-methoxyphenyl)nitroethane was 0.183 g.

Nickel chloride monohydrate (0.107 g, 0.404 mmol) was dissolved in 5 mLof methanol, followed by the addition of sodium borohydride (0.05 g, 1.2mmol). After stirring for 5 minutes,1-ethyl-1-methyl-2-(4-methoxyphenyl)nitroethane (0.18 g, 0.807 mmol) in3 mL of methanol was added, and stirred for 5 minutes. Sodiumborohydride (0.11 g, 2.83 mmol) was then added in portions over 5minutes. The 20 reaction was then stirred overnight under a hydrogenballoon. The reaction mixture was filtered, and the methanol was removedon a rotary evaporator. The residue was taken up in ether and dilutesodium hydroxide. The ether layer was separated, washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated. The yieldof 1-ethyl-1-methyl-2-(4-methoxy-phenyl)ethylamine was 0.127 grams.

Using the method of Example 6, supra, 1,2-epoxy-3-phenoxypropane (0.086g, 0.57 mmol) and 1-ethyl-1-methyl-2-(4-methoxyphenyl)ethylamine (0.11g, 0.57 mmol) were used to prepare 90 mg of the title compound as awhite solid: GC/EI-MS, m/z, (rel. int.) 314 (M-29,2), 223 (15), 222(100), 128 (6), 121 (20), 107 (5), 84 (10), 78 (5), 77 (12), 72 (5), 56(7).

EXAMPLE 65: Preparation ofN-(2-Hydroxy-3-phenoxypropyl)-1,1-diethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 114 ##STR65##

Anhydrous cerium (III) chloride (13.6 g, 55.2 mmol) was suspended in 80mL of dry terahydrofuran, and stirred under nitrogen for 16 hours. Thissuspension was cooled in an ice bath, and ethylmagnesium chloride (27.6mL, 55.18 mmol, 2M solution in tetrahydrofuran) was added over 5minutes. After stirring for 1 hour, methyl 4-methoxyphenylacetate (3.98g, 22.07 mmol) was added to the suspension and stirred for another 2hours. The reaction was then partitioned between ether and saturatedammonium chloride. The ether layer was separated, washed with diluteHCl, water, and saturated brine, dried over anhydrous sodium sulfate,and concentrated. The yield of 1,1-diethyl-2-(4-methoxyphenyl)ethanolwas 4.65 g.

Powdered sodium cyanide (1.18 g, 24 mmol) was placed in a flask andcovered with 5.5 mL of acetic acid. A mixture of sulfuric acid (3 mL)and acetic acid (2.75 mL) was cooled to 0° C. and then added to thecyanide suspension over a period of 3 minutes. The mixture was stirredfor 30 minutes at room temperature, followed by the addition of1,1-diethyl-2-(4-methoxyphenyl)ethanol (4.6 g, 22 mmol). The mixture wasstirred overnight then poured into ice and sodium hydroxide. The productwas extracted with ether, and the ether layer dried over anhydroussodium sulfate, and concentrated. The residue was suspended in 20%sodium hydroxide and refluxed overnight under nitrogen. The reaction wascooled, diluted with water, and extracted with ether. The ether layerwas separated, washed with saturated brine, dried over anhydrous sodiumsulfate, and concentrated. The residue was purified by reversed-phaseHPLC (C-18 using 0.1% HCl/acetonitrile as the elutant) to give 1.91 g of1,1-diethyl-2-(4-methoxyphenyl)ethylamine.

Using the method of Example 6, supra, 1,2-epoxy-3-phenoxypropane (0.15g, 1.0 mmol) and 1,1-diethyl-2-(4-methoxyphenyl)ethylamine (0.249 g, 1.2mmol) were used to prepare 244 mg of the title compound as a whitesolid: GC/EI-MS, m/z, (rel. int.) 328 (M-29,6), 237 (17), 236 (100), 121(22), 106 (5), 98 (7), 78 (5), 77 (11), 70 (7), 56 (5).

EXAMPLE 66: Preparation of(R)-N-[2-Hydroxy-3-(2,3-dichlorophenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine Hydrochloride, Compound 115 ##STR66##

2,3-Dichlorophenol (0.69 g, 4.24 mmol) was dissolved in 15 mL ofacetone, followed by the addition of powdered potassium carbonate (1.6g, 11.57 mmol). This mixture was stirred for 2 hours then(2R)-(-)-glycidyl 3-nitrobenzenesulfonate was added and stirredovernight. The reaction was worked up by pouring into water and ether.The ether layer was separated, washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated. The yield of(R)-2,3-dichlorophenyl glycidyl ether was 0.837 g.

Using the method of Example 6, supra, (R)-2,3-dichlorophenyl glycidylether (0.837 g, 3.82 mmol) and1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (0.75 g, 4.18 mmol) were usedto prepare 860 mg of the title compound as a white solid: GC/El-MS, m/z,(rel. int.) 382 (M-15,0.1), 280 (11), 278 (64), 277 (16), 276 (100), 163(10), 121 (35), 77 (10), 71 (24), 70 (27), 58 (12).

EXAMPLE 67: Preparation of(S)-N-[2-Hydroxy-3-(2,3-dichlorophenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine Hydrochloride, Compound 116 ##STR67##

2,3-Dichlorophenol (0.69 g, 4.24 mmol) was dissolved in 15 mL ofacetone, followed by the addition of powdered potassium carbonate (1.6g, 11.57 mmol). This mixture was stirred for 2 hours then(2S)-(+)-glycidyl 3-nitrobenzenesulfonate was added and stirredovernight. The reaction was worked up by pouring into water and ether.The ether layer was separated, washed with saturated brine, dried overanhydrous sodium sulfate, and concentrated. The yield of(S)-2,3-dichlorophenyl glycidyl ether was 0.84 g.

Using the method of Example 6, supra, (S)-2,3-dichlorophenyl glycidylether (0.84 g, 3.82 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine(0.75 g, 4.18 mmol) were used to prepare 860 mg of the title compound asa white solid: GC/EI-MS, m/z, (rel. int.) 382 (M-15,0.1), 280 (10), 279(9), 278 (63), 276 (100), 163 (11), 121 (28), 77 (7), 71 (21), 70 (23),58 (10).

EXAMPLE 68: Preparation ofN-(2-Hydroxy-3-phenoxypropyl)-1,1-dimethyl-2-(4-methoxy-3-methylphenyl)ethylamine Hydrochloride, Compound 117 ##STR68##

Using the method of Example 64, supra, 4-hydroxy-3-methylbenzyl alcohol(1.0 g, 7.25 mmol), 2-nitropropane (5 mL), and tetrabutylammoniumfluoride (0.38 g, 0.145 mmol) were used to prepare 0.8 g of1,1-dimethyl-2-(4-methoxy-3-methylphenyl)ethylamine.

Using the method of Example 6, supra, 1,2-epoxy-3-phenoxypropane (0.151g, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxy-3-methylphenyl)ethylamine(0.2 g, 1.0 mmol) were used to prepare 130 mg of the title compound as awhite solid: GC/EI-MS, m/z, (rel. int.) 328 (M-15,0.1), 209 (14), 208(100), 177 (5), 135 (14), 114 (5), 91 (6), 76 (9), 71 (8), 70 (13), 58(5).

EXAMPLE 69: Preparation ofN-[2-Hydroxy-3-(2-cyano-3-methoxyphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine Hydrochloride, Compound 118 ##STR69##

Powdered sodium cyanide (9.0 g, 184 mmol) and 2,6-dimethoxybenzonitrilewere added to 50 mL of dimethylsulfoxide and heated to 145° C. for 110min under nitrogen. The reaction was cooled and poured into ether anddilute HCl. The ether layer was separated, washed twice with diluteacid, once with saturated brine, dried over anhydrous sodium sulfate,and concentrated. The yield of 2-cyano-3-methoxyphenol was 8.1 g.

2-Cyano-3-methoxyphenol (1 g, 6.7 mmol) and powdered potassium carbonate(2.78 g, 20.1 mmol) were stirred in 15 mL of acetone for 5 minutes,followed by addition of epibromohydrin (1.38 g, 10.1 mmol). The mixturewas stirred for 72 hours then poured into water/ether. The ether layerwas separated, washed with sodium carbonate and saturated brine, driedover anhydrous sodium sulfate, and concentrated. The resulting crudesolid was triturated with ether/hexane, filtered, and dried under vacuumto give 0.44 g of 2-cyano-3-methoxyphenyl glcidyl ether.

Using the method of Example 6, supra, 2-cyano-3-methoxyphenyl glcidylether (0.205 g, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine(0.215 g, 1.2 mmol) were used to prepare 265 mg of the title compound asa white solid: ¹ H-NMR (CDCl₃) ∂ 9.6 (1H, br s), 8.2 (1H, br s), 7.4(1H, t), 7.15 (2H, d), 6.8 (2H, d), 6.6 (1H, d), 6.53 (1H, d), 4.75 (1H,m), 4.25 (2H, m), 3.87 (3H, s), 3.77 (3H, s), 3.43 (2H, m), 3.12 (2H,dd), 1.45 (3H, S), 1.41 (3H, s). ¹³ C-NMR ∂ 162.9, 162, 159.3, 135.5,132.4, 127, 114.7, 114.4, 105.6, 104.6, 92.2, 71.4, 66.1, 61.9, 56.8,55.8, 45.4, 43.8, 23.5, 23.3.

EXAMPLE 70: Preparation ofN-[2-Hydroxy-3-(3-chloro-2-cyanophenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 119 ##STR70##

Using the method of Example 69, supra, 3-chloro-2-cyanophenol (madeusing the method of Example 60, supra) (0.48 g, 3.13 mmol), potassiumcarbonate (1.3 g, 9.38 mmol), and epibromohydrin (0.86 g, 6.25 mmol)were used to prepare 93 mg of 3-chloro-2-cyanophenyl glycidyl ether.

Using the method of Example 6, supra, 3-chloro-2-cyanophenyl glycidylether (0.093 g, 0.44 mmol) and 1,1-dimethyl-(4-methoxyphenyl)ethylamine(0.095 g, 0.53 mmol) were used to prepare 134 mg of the title compoundas a white solid: ¹ H-NMR (CDCl₃) ∂ 9.68 (1H, br s), 8.2 (1H, br s), 7.4(1H, t), 7.15 (2H, d), 7.03 (1H, d), 6.95 (1H, d), 6.8 (2H, d), 5.7 (1H,br s), 4.8 (1H, m), 4.3 (2H, d), 3.75 (3H, s), 3.4 (2H, m), 3.13 (2H,dd), 1.44 (3H, s), 1.40 (3H, s).

EXAMPLE 71: Preparation ofN-(2-Hydroxy-3-phenoxypropyl)-1,1-dimethyl-2-(2-naphthyl)ethylamineHydrochloride, Compound 120 ##STR71##

Using the method of Example 52, supra, 2-aminomethylnaphthalene (2.51 g,16 mmol) was used to prepare 1.9 g of1,1-dimethyl-2-(2-naphthyl)ethylamine.

Using the method of Example 6, supra, 1,2-epoxy-3-phenoxypropane (0.163g, 1.1 mmol) and 1,1-dimethyl-2-(2-naphthyl)ethylamine (0.26 g, 1.3mmol) were used to prepare 243 mg of the title compound as a whitesolid: GC/EI-MS, m/z, (rel. int.) 334 (M-15,0.1), 209 (14), 208 (100),141 (16), 115 (7), 76 (5), 70 (7).

EXAMPLE 72: Preparation ofN-(2-Hydroxy-3-phenoxy)propyl)-1,1-dimethyl-2-(3,4-dimethylphenyl)ethylamine Hydrochloride, Compound 121 ##STR72##

Using the method of Example 52, supra, 3,4-dimethylbenzylamine (5 g, 37mmol) was used to prepare 2.29 g of1,1-dimethyl-2-(3,4-dimethylphenyl)ethylamine.

Using the method of Example 6, supra, 1,2-epoxy-3-phenoxypropane (0.165g, 1.1 mmol) and 1,1-dimethyl-2-(3,4-dimethylphenyl)ethylamine (0.22 g,1.2 mmol) were used to prepare 268 mg of the title compound as a whitesolid: GC/El-MS, m/z, (rel. int.) 312 (M-15,1), 209 (14), 208 (100), 133(5), 119 (13), 114 (5), 107 (5), 91 (5), 76 (10), 71 (8), 70 (14), 58(6).

EXAMPLE 73: Preparation of(R)-N-[2-Hydroxy-3-(2-cyanophenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 122 ##STR73##

Using the method of Example 60, supra, 2-cyanophenol (0.54 g, 4.5 mmol),sodium hydride (0.188 g, 4.7 mmol), and (2R)-(-)-glycidyl3-nitrobenzenesulfonate (1.06 g, 4.1 mmol) were used to prepare 350 mgof (R)-2-cyanophenyl glycidyl ether.

Using the method of Example 6, supra, (R)-2-cyanophenyl glycidyl ether(0.35 g, 2.0 mmol) and 1,1-dimethyl-(4-methoxyphenyl)ethylamine (0.35 g,1.96 mmol) were used to prepare 600 mg of the title compound as a whitesolid: ¹ H-NMR (CDCl₃) ∂ 9.7 (1H, br s), 8.2 (1H, br s), 7.5 (2H, m),7.15 (2H, d), 7.0 (2H, m), 6.8 (2H, d), 4.8 (1H, br m), 4.25 (2H, m),3.75 (3H, s), 3.45 (2H, m), 3.12 (2H, dd), 1.45 (3H, s), 1.41 (3H, s).

EXAMPLE 74: Preparation ofN-(2.10-Dihydroxydecyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 123 ##STR74##

Using the method of Example 9, supra, 1,2-epoxy-10-hydroxydecane (172mg, 1 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (230 mg, 1.5mmol) were used to prepare the hydrochloride salt of the title compound.MPLC of the free amine (silica gel, 1% MeOH/CHCl₃), followed bytreatment with an excess of 1M HCl/ether, yielded 130 mg of the titlecompound as a white powder: GC/EI-MS, m/z (rel. int.) 336 (M⁺ -15,0.1),231 (14), 230 (100), 212 (9), 163 (10), 122 (5), 121 (42), 91 (8), 78(6), 77 (5), 71 (13), 70 (11), 58 (8), 55 (8), 41 (6).

EXAMPLE 75: Preparation ofN-[2-hydroxy-3-(3,4-methylene-dioxyphenyl)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)-ethylamineHydrochloride, Compound 124 ##STR75##

Safrole oxide was prepared by stirring a solution of safrole (1.48 mL,10 mmol) and m-chloroperoxybenzoic acid (2.70 g, 11 mmol) in methylenedichloride (25 mL) overnight. The reaction was quenched by pouring intowater (50 mL). The aqueous was extracted with ether (3×25 mL). Theorganic layers were combined and washed with 10% aqueous sodium sulfate(2×25 mL), saturated aqueous sodium bicarbonate (3×25 mL), and brine (25mL). The organic phase was dried over magnesium sulfate and the solventswere removed in vacuo. The resulting yellow oil was used without furtherpurification.

To a solution of safrole oxide (196 mg, 1.1 mmol) in acetonitrile (1.0mL) was added lithium perchlorate (107 mg). The solution was stirred atambient temperature to dissolve all of the solid lithium perchlorate. Tothis solution was added 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (180mg, 1.0 mmol) and the reaction was stirred at 50° C. overnight. To thecooled reaction mixture was added water (5 mL) and was subsequentlyextracted with methylene dichloride (3×1 mL). The combined organicphases were washed with water (1 mL) and brine (1 mL) and dried overmagnesium sulfate. The crude orange oil was purified (MPLC, silica gel,1% MeOH/CHCl₃) and dissolved in methylene dichloride (5 mL). Thehydrochloride salt was prepared by adding an excess of 1M HCl/ether. Thesolvents were removed in vacuo to yield 139 mg of thick oil: GC/EI-MS,m/z (rel. int.) 342 (M⁺,0.1), 237 (15), 236 (100), 163 (5), 136 (6), 135(61), 121 (23), 78 (7), 77 (13), 70 (15), 58 (7).

EXAMPLE 76: Preparation ofN-[2-hydroxy-3-(3,4-methylene-dioxyphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)-ethylamineHydrochloride, Compound 125 ##STR76##

Using the method of Example 9, supra,1,2-epoxy-3-(3,4-methylenedioxyphenoxy)propane (194 mg, 1 mmol) and1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (180 mg, 1 mmol) were used toprepare the hydrochloride salt of the title compound. MPLC of the freeamine (silica gel, 1% MeOH/CHCl₃), followed by treatment with an excessof 1M HCl/ether, yielded 88 mg of a white powder: GC/EI-MS, m/z (rel.int.) 374 (M⁺,0.0), 253 (15), 252 (100), 137 (8), 121 (16), 114 (8), 71(12), 70 (8).

EXAMPLE 77: Preparation ofN-[2-hydroxy-3-(6-phenylhexanoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine.Compound 126 ##STR77##

Using the method of Example 9, supra, 6-phenylhexylglycidyl ether (337mg, 1.44 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (180 mg, 1mmol) were used to prepare the title compound. Preparative TLC (20 cm×20cm×2 mm silica, eluted with 1% MeOH/CHCl₃) was used to purify thematerial and yielded 275 mg of free base: GC/El-MS, m/z (rel. int.) 398(M⁺ -15,0.1), 293 (21), 292 (100), 163 (10), 121 (19), 114 (9), 91 (5),90 (45), 71 (13), 70 (14), 58 (9).

EXAMPLE 78: Preparation ofN-[2-hydroxy-3-(4-phenylbutanoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine.Compound 127 ##STR78##

Using the method of Example 9, supra, 4-phenylbutyl glycidyl ether (348mg, 1.5 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (268 mg,1.5 mmol) were used to prepare the title compound. Preparative TLC (20cm×20 cm×2 mm silica, eluted with 5% MeOH/CHCl₃) was used to purify thematerial and yielded 275 mg of free base: GC/EI-MS, m/z (rel. int.) 370(M⁺ -15,0.1), 265 (19), 264 (100), 163 (11), 121 (19), 114 (9), 90 (43),71 (10), 70 (12), 58 (7).

EXAMPLE 79: Preparation ofN-(2-hydroxy-3-phenoxypropyl)-1,1-dimethyl-2-(3-fluoro-4-methoxyphenyl)ethylamine. Compound 128 ##STR79##

Using the method of Example 6, supra, phenyl glycidyl ether (150 mg, 1.1mmol) and 1,1-dimethyl-2-(3-fluoro-4-methoxyphenyl)ethylamine (197 mg, 1mmol) were used to prepare the title compound. The title compoundcrystallized on standing to yield 169 mg of small crystals: GC/EI-MS,m/z (rel. int.) 332 (M⁺ -15,0.1), 209 (16), 208 (100), 139 (13), 133(5), 114 (7), 107 (6), 77 (11), 71 (12), 70 (20), 58 (9).

EXAMPLE 80: Preparation ofN-(2-hydroxy-3-phenoxypropyl)-1,1-dimethyl-2-(2-fluoro-4-methoxyphenyl)ethylamineHydrochloride, Compound 129 ##STR80##

Using the method of Example 6, supra, phenyl glycidyl ether (150 mg, 1.1mmol) and 1,1-dimethyl-2-(2-fluoro-4-methoxyphenyl)ethylamine (197 mg, 1mmol) were used to prepare the title compound. Preparative HPLC (C₁₈reversed-phase, eluted with 1% HCl/CH₃ CN gradient) was used to purifythe compound, yielding 301 mg of a white powder: GC/EI-MS, m/z (rel.int.) 332 (M⁺ -15,1), 209 (15), 208 (100), 139 (14), 114 (5), 107 (5),77 (6), 71 (7), 70 (13), 58 (5).

EXAMPLE 81: Preparation ofN-[2-hydroxy-3-(5-methoxy-1-napthoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 130 ##STR81##

Potassium carbonate (13 mmol) was added to a solution of 1,5-dihydroxynapthalene (6.2 mmol) in acetone in a sealed vacuum tube. The tube washeated to 70° C. for 30 minutes. Iodomethane (9.4 mmol) was added andthe tube heated to 70° C. overnight.

The reaction mixture was partitioned between ether and 10% aqueous HCl.The ether layer was separated and extracted with 0.5M KOH. The waterlayer was separated and acidified with 10% aqueous HCl and extractedinto ether. The ether layer was separated and dried over magnesiumsulfate and evaporated to a solid. The solid was purified using reversephase HPLC using a acetonitrile/0.1% HCl gradient yielding 179 mg1-hydroxy-5-methoxy napthalene.

Sodium hydride (60% suspension in mineral oil, 1 mmol) was added to asolution of 1-hydroxy-5-methoxy napthalene (1 mmol) and stirred 10minutes. Epichlorohydrin (1 mmol) was added and the reaction stirred at70° C. for 72 hours. The reaction mixture was diluted with 1 liter ofsaturated sodium chloride solution and extracted into ether. The etherlayer was then washed with water, separated and dried over anhydroussodium sulfate and evaporated to give 5-methoxynapthalene glycidylether.

Using the method of Example 6, supra, 5-methoxynapthalene glycidyl ether(1 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (1 mmol) yielded161 mg of the title compound as a white solid: GC/EI-MS, m/z (rel. int.)360 (M+, 1), 289 (18), 288 (100), 173 (8), 121 (20), 71 (18), 70 (12).

EXAMPLE 82: Preparation ofN-[2-hydroxy-3-(2-cyanocyclohexyloxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride, Compound 131 ##STR82##

Sodium hydride (60% suspension in mineral oil, 60 mg, 1.59 mmol) wasadded to a solution of trans-2-cyanocyclohexanol inN,N-dimethylformamide (2.0 mL) and stirred for 10 minutes at roomtemperature. Epibromohydrin (0.22 g, 1.59 mmol) was then added and thereaction stirred for an additional 3 hours. The solution was partitionedbetween diethyl ether/water, and the layers separated. The ether layerwas washed with water (3×100 mL) and dried over magnesium sulfate andevaporated to give 0.17 g of 2-cyanocyclohexyl glycidyl ether.

Using the method of Example 6, supra, 2-cyanocyclohexyl glycidyl ether(0.94 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (1.17 mmol)yielded 55 mg of the title compound as a white solid: GC/EI-MS, m/z(rel. int.) 360 (M+, 1), 239 (100), 121 (22), 240 (14), 70 (11), 163(8), 71 (8), 81 (7).

EXAMPLE 83: Synthesis of (R/S)-1-[[2.2-dimethyl-(4'methoxy)phenethyl]]amino-2-hydroxy-4(1'-naphthyl)-butane. Compound 162 ##STR83##

A solution of 1-chloromethylnaphthaline (750 uL, 5 mmol, Aldrich) inanhydrous ether (10 mL) was added dropwise to 25 mL of allyl magnesiumbromide (1M in ether) over 30 minutes. The resulting mixture was heatedat reflux for 14 hours. After cooling the reaction to room temperature,it was quenched with 25 mL of saturated NH₄ Cl (aqueous). The layerswere separated and the organic layer was washed with brine, dried overNa₂ SO₄, filtered and evaporated to give 1 g of 1-but-3-enyl-naphthalanethat was carried without further purification.

1-But-3-enyl-naphthaline (1 g) from above was added to a solution of 50%mCPBA (2.1 g) in CH₂ Cl₂ (50 mL) and the reaction stirred at roomtemperature for 48 hours. The material was diluted with CH₂ Cl₂ and wasextracted with sodium sulfite (aqueous) and NaHCO₃ (aqueous), dried overMgSO₄, filtered and evaporated to give 1-[(2-oxoaryl)ethyl]-naphthaline(1 g) that was carried without further purification.

A solution of 1-[(2-oxoaryl)ethyl]-naphthaline (1 g) and1,1-dimethyl-2(4-methoxyphenyl) ethylamine (985 mg, 5.5 mmol) in ethanol(25 mL) was heated at reflux for 12 hours. The reaction was evaporatedand the residue dissolved in 4N HCl/dioxane. Upon addition of ether,crystals formed and were subsequently collected and dried in a vacuumoven to give 1.4 g of(R/S)-1-]]2,2-dimethyl-(4'methoxy)-phenethyl]]amino-2-hydroxy-4(1'-naphthyl)-butane.ESMS [(M+H]⁺ =378, ¹ H NMR (CDCl₃, 360MHz) @300° K. δ 8.06 (1H, d of d),7.83 (1H, d of d), 7.78-7.61 (2H, m), 7.49-7.35 (3H, m), 7.09-7.02 (2H,m), 6.84-6.79 (2H, m), 3.76 (3H, s), 3.61 (1H,m), 3.33-3.09 (2H, m),2.77-2.72 (1H, d of d), 2.62 (2H, S), 2.47-2.42 (1H, m), 1.85-1.82 (2H,m), 1.04 (6H, s).

EXAMPLE 84 Synthesis of(R/S)-1-[[2.2-dimethyl-(4'methoxy)phenethyl]]amino-2-hydroxy-4[1'-2,3-dichlorophenyl)]-butane,Compound 163 ##STR84##

Starting from 2,3-dichlorobenzylchloride (1 g, 5 mmol) and following thethree step procedure described in Example 83, 660 mg of(R/S)-1-[[2,2-dimethyl-(4'methoxy)-phenethyl]]amino-2-hydroxy-4[1'-(2,3-dichlorophenyl)]-butanewas synthesized and isolated as white crystals. ESMS [M+H]⁺ =396 ¹ H NMR(CDCl₃, 360 MHz) @ 300° K. δ7.3 (1H, d of d), 7.18 (1H, d of d),7.10-7.03 (3H, m), 6.82-6.80 (2H, m), 3.78 (3H, s), 3.47 (1H, m),2.97-2.83 (2H, m), 2.74 (1H, m) 2.60 (2H, s), 2.43-2.37 (1H, m), 1.71(2H, m), 1.04 (6H, s).

EXAMPLE 85: Synthesis of(R/S)-1-nitro-5-hydroxy-6-[1,1-dimethyl-2-(4-methoxyphenyl)]hexane.Compound 164 ##STR85##

Starting from 6-nitro-1-hexene (1 g, 7.75 mmol) and following the twolast steps described in Example 83, 1 g of(R/S)-1-nitro-5-hydroxy-6-[1,1-dimethyl-2(4-methoxyphenyl)]hexane wassynthesized and isolated as tan crystals. ESMS [M+H]⁼ =325 ¹ H NMR(CDCl₃, 360 MHz) @ 300° K. δ 7.00 (4H, d of d), 4.37 (2H, t), 3.77 (3H,s), 3.49 (1H, m), 2.74 (1H, d of d), 2.61 (2H, s), 2.35 (1H, m) 2.03(2H, m), 1.60-1.43 (4H, m) 1.08 (6H, s).

EXAMPLE 86:N-[2(R)-Hydroxy-3-[(2.3-dichloro-4-dipropylsulfamoyl)phenoxyl-1-propyl]-N-[1,1-dimethyl-2-(4-methoxyphenyl)ethyl]aminehydrochloride salt Compound 165 ##STR86##

a) (2,3-Dichloro-4-methoxy)phenylsufonylchloride 2,3-dichloroanisole(Aldrich, 9.0 g, 50.8 mmol) was utilized in the method of H. Harada etal., Chem Pharm Bull (1987) 35(8) 3195-3214 to give the title compoundas a white solid (13.3, 95%).

b) N,N-Dipropyl-(2,3-dichloro-4-methoxy)phenylsulfonamide.

The compound of Example 86a (8.0 g, 29.0 mmol) was dissolved in CH₂ Cl₂(200 mL) and dipropylamine (11.9 mL, 87.1 mmol) in EtOH (40 mL) wasadded at -20° C. The ice bath was removed and the mixture stirred 1.5hours. The mixture was poured into H₂ O and extracted with CH₂ Cl₂. Thecombined organic extracts were washed with H₂ O and brine, concentratedin vacuo and azeotroped with toluene to yield the title compound as alight brown-tinted oil (9.8 g, 100%). 1H NMR (400 MHz, CDCl₃) d 8.05 (d,J=10 Hz, 1H), 6.92 (d, J=10 Hz, 1H), 4.00 (s, 3H), 3.23 (t, J=8, 17 Hz,4H), 1.52 (m, 4H), 0.83 (t, J=8, 13 Hz, 6H).

c) N,N-Dipropyl-2,3-dichloro-4-hydroxyphenylsulfonamide.

The compound from Example 86b (10.0 g, 29.4 mmol), I₂ (14.9 g, 58.8mmol) and trimethylphenylsilane (15.1 mL, 88.2 mmol) were stirredtogether and heated to 110° C. for 18 hours. The mixture was poured intoaqueous Na₂ S₂ O₃, extracted with EtOAc, dried (MgSO₄), concentrated todryness in vacuo and purified by column chromatography (silica gel, 40%EtOAc in hexanes) to give a clear oil (9.2 g, 86%). 1H NMR (400 MHz,CDCl₃) d 7.98 (d, J=10 Hz, 1H), 7.05 (d, J=10 Hz, 1H), 6.29 (brs, 1H),3.24(t, J=9, 18 Hz, 4H), 1.56 (m, 4H), 0.84 (t, J=8,14 Hz, 6H).

d) [2,3-Dichloro-4-(N,N-dipropylsulfamoyl)]phenyl glycidyl ether.

The compound of Example 86c (5.0 g, 15.3 mmol), K₂ CO₃ (6.4 g, 46.0mmol), and (2R)-(-)-glycidyl 3-nitrobenzene-sulfonate (5.6 g, 15.3 mmol)were heated in acetone (250 mL) to reflux 18 hours. The solvent wasconcentrated in vacuo to half volume, poured into H₂ O, extracted withEtOAc, the combined organic extracts were dried (MgSO₄), evaporated andpurified by column chromatography (silica gel, 40% EtOAc in hexanes) togive the title compound as a clear oil (4.9 g, 84%). 1H NMR (400 MHz,CDCl₃) d 8.04 (d, J=8 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 4.45 (dd, J=1, 9Hz, 1H), 4.11 (dd, J=7, 11 Hz, 1H), 3.44 (m, 1H), 3.24 (t, J=9, 18 Hz,4H), 2.97 (m,1H), 2.87(m, 1H), 1.52 (m, 4H), 0.84 (t, J=6,14 Hz, 6H)

e) N-[2(R)-Hydroxy-3-[(2,3-dichloro-4-dipropylsulfamoyl)phenoxy]-1-propyl]-N-[1,1-dimethyl-2-(4-methoxyphenyl)ethyl] aminehydrochloride salt.

The compound from Example 86d (1.6 g, 4.2 mmol),1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (0.75 g, 4.2 mmol) and LiClO₄(0.89 g, 8.4 mmol) were dissolved in CH₃ CN (150 mL) and refluxed 18hours. The mixture was concentrated in vacuo and purified by columnchromatography (silica gel, 8% MeOH in CH₂ Cl₂) to yield the titlecompound as a white solid (1.0 g, 44%). This was converted to the HClsalt by adding 1.7 mL of 1M HCl in MeOH, stirring 5 minutes,concentrating in vacuo, azeotroping with toluene then CH₂ Cl₂. MS (ES)m/e 561.1[M+H+]; 1H NMR (400 MHz, CDCl₃) d 9.94 (bs, 1H), 8.02 (d, J=8HZ, 1H), 7.14 (d, J=8 HZ, 2H), 6.96 (d, J=8 HZ, 1H), 6.86 (d, J=7 Hz,1H), 4.78 (m, 1H), 4.30 (m, 1H), 4.20 (m, 1H), 3.80 (s, 3H), 3.68 (m,2H), 3.43 (bs, 1H), 3.23 (t, J=7, 14 Hz, 4H), 3.12 (m, 2H), 1.50 (q,J=5, 13 Hz, 4H), 1.43 (s, 3H), 1.38 (s, 3H), 0.83 (t, J=8,13, 6H).

EXAMPLE 87: Additional compounds

Additional compounds were synthesized using techniques along lines asthose described above. Examples of such compounds include the following:

Compound 1:N-[2-hydroxy-3-(2-hydroxybenzimidazol-4-oxyl)propyl]-1,1-dimethyl-2-4-methoxyphenyl)ethylamine.

Compound 14:(R)-N-[2-hydroxy-3-(1-naphthoxy)propyl]-1-methyl-3-methoxybenzylamine.

Compound 22:N-(3-phenylpropyl)-1,1-dimethyl-2(4-methoxyphenyl)ethylamine.

Compound 24:N-(4-phenylbutyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine.

Compound 34: N-(Benzyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine.

Compound 36:N-(4-phenoxybutyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine.

Compound 42: N-(3-(1-napthoxy)propyl)-1,1-dimethyl-2-(4-methoxyphenyl).

Compound 52:N-[2-hydroxy-3-(2-acetamidophenoxy)propyl]-1,1-dimethyl-2(4-methoxyphenyl)ethylamine.

Compound 53:N-(2-phenoxyethyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine.

Compound 54:N-2-hydroxy-3-(4-tert-butylphenoxy)propyl]-1,1-dimethyl-2-phenylethylamine.

Compound 55:N-[2-hydroxy-3-(1-naphthoxy)propyl]-1,1-dimethyl-2-phenylethylamine.

Compound 58:N-[2-hydroxy-3-(4-acetamidophenoxy)propyl]-1,1-dimethyl-2(4-methoxyphenyl)ethylamine.

Compound 60:N-[2-hydroxy-3-(2-phenylphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine.

Compound 61:N-[2-hydroxy-3-(3-phenylphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine.

Compound 62:N-[2-Hydroxy-3-(4-phenylphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine.

Compound 84:N-(2-Phenylethyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine.

Compound 92:N-(2-hydroxy-3-phenoxypropyl)-1,1-dimethyl-2-(1-naphthyl)ethylamine.

Compound 93:N-(2-hydroxy-3-cyclohexoxypropyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine.

Compound 102:N-(2-hydroxy-3-phenoxypropyl)-1,1-dimethyl-2-(4-ethoxyphenyl)ethylamine.

Compound 132:N-[2-hydroxy-3-(3,4-dimethoxyphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 390 (M+,0.0), 269 (17), 268(100), 163 (6), 153 (5), 121 (21), 114 (17), 77 (5), 71 (19), 70 (17),58 (7).

Compound 133:N-[2-hydroxy-3-(3,5-dimethoxyphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 390 (M+,0.0), 269 (16), 268(100), 193 (9), 163 (8), 154 (7), 121 (24), 114 (46), 76 (6), 71 (11),70 (18).

Compound 134:N-[2-hydroxy-3-(2-carbomethoxyphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; ¹ H NMR (CDCl₃) ∂ 1.42 (s, 3H), 1.44 (s, 3H), 3.2 (dd,2H), 3.3-3.6 (bm, 2H), 3.7 (s, 3H), 3.8 (s, 3H), 4.1-4.4 (m, 3H), 4.7(m, 1H), 6.8 (d, 2H), 7.0 (m, 2H), 7.2 (d, 2H), 7.5 (t, 1H), 7.8 (d,1H), 8.8 (m, 1H), 9.3 (m, 1H).

Compound 135:N-[2-hydroxy-3-(4-methylphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 328 (M-15,0.1), 223 (15), 222(100), 163 (6), 147 (6), 121 (23), 114 (9).

Compound 136:N-[2-hydroxy-3-(2,3-dichlorophenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 382 (M-15,0.1), 280 (10), 279(9), 278 (62), 276 (100), 163 (11), 121 (28).

Compound 137:N-[2-hydroxy-3-(3,5-dichlorophenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 382 (M-15,1), 280 (11), 279(9), 278 (65), 277 (16), 276 (100), 163 (8), 146 (5), 144 (5).

Compound 138:N-[2-hydroxy-3-(2,4-dichlorophenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 382 (M-15,1), 280 (11), 279(9), 278 (65), 277 (5), 276 (100), 163 (10), 161 (6), 132 (5).

Compound 139:N-[2-hydroxy-3-(3,4-dichlorophenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 382 (M-15,0.1), 279 (10), 279(9), 278 (63), 276 (100), 163 (9), 146 (5), 121 (29).

Compound 140:N-[2-hydroxy-3-(2,5-dichlorophenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 382 (M-15,0.1), 280 (11), 279(9), 278 (64), 276 (100), 163 (9), 161 (5), 121 (29), 113 (8).

Compound 141:N-[2-hydroxy-3-(4-ethylphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 342 (M-15,0.1), 237 (15), 236(100), 163 (5), 121 (19) , 114 (7).

Compound 142:N-[2-hydroxy-3-(2-cyanophenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 339 (M-15,1), 234 (15), 233(100), 163 (5), 121 (14).

Compound 143:N-[2-hydroxy-3-(3-nitrophenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 359 (M-15,0.1), 254 (15), 253(100), 163 (5), 121 (15).

Compound 144:N-[2-hydroxy-3-(4-ethoxyphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 358 (M-15,0.1), 253 (17), 252(100), 163 (6), 121 (21), 114 (8), 108 (8).

Compound 145:N-[2-hydroxy-3-(4-iso-propylphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 356 (M-15,0.1), 251 (18), 250(100), 163 (7), 121 (23), 117 (7), 114 (8).

Compound 146:N-[2-hydroxy-3-(3-iso-propylphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 356 (M-15,0.1), 251 (18), 250(100), 163 (6), 121 (21), 117 (5), 114 (10), 91 (9).

Compound 147:N-[2-hydroxy-3-(3-ethoxyphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 358 (M-15,1), 253(16), 252(100), 163 (5), 121 (20), 114 (12), 77 (5).

Compound 148:N-[2-hydroxy-3-(2-n-propylphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 356 (M-15,1), 251(17), 250(100), 163 (6), 121 (34), 114 (9), 107 (6), 90 (17), 78 (9), 77 (10), 71(17).

Compound 149:N-[2-hydroxy-3-(4-n-propylphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 356 (M-15,0.8), 251(18), 250(100), 163 (5), 121 (19), 114 (7), 110 (5), 107 (7), 91 (6).

Compound 150:N-[2-Hydroxy-3-(3-ethylphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 342 (M-15,0.6), 237(16), 236(100), 163 (5), 121 (21), 114 (6), 105 (5), 90 (6).

Compound 151:N-[2-hydroxy-3-(2-ethylphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 342 (M-15,1), 237 (16), 236(100), 163 (5), 121 (17), 114 (7), 91 (6), 77 (7).

Compound 152:N-[2-hydroxy-3-(4-trifluoro-methoxyphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 398 (M-15,2), 293(15), 292(100), 121 (20), 77 (5).

Compound 153:N-[2-hydroxy-3-(2-iso-propylphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 356 (M-15,1), 251 (19), 250(100), 163 (5), 122 (5), 121 (53), 114 (8), 104 (6),103 (6), 91 (24), 77(14).

Compound 154:N-[2-hydroxy-3-(3-trifluoro-methoxyphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 398 (M-15,0.1), 293 (15), 292(100), 163 (7), 121 (18).

Compound 155:N-[2-hydroxy-3-(2,6-dichlorophenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 382 (M-15,1), 279 (11), 279(9), 277 (64), 275 (100), 163 (11), 163 (5), 161 (6), 121 (33), 114(12).

Compound 156:N-[2-hydroxy-3-(3,5-bistrifluoromethylphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 450 (M-15,0.1), 345 (16), 344(100), 213 (5), 163 (8), 121 (20).

Compound 157:N-[2-hydroxy-3-(3-chloro-5-methoxyphenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 378 (M-15,0.1), 275 (5), 274(34), 273 (16), 272 (100), 163 (5), 121 (17), 114 (8).

Compound 158:N-[2-hydroxy-3-(4-nitrophenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 359 (M-15,1), 254 (14), 253(100), 121 (12).

Compound 159:N-[2-hydroxy-3-(2-nitrophenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 359 (M-15,0.1), 254 (15), 253(100), 163 (6), 121 (17), 114 (10), 96 (5), 78 (5).

Compound 160:N-[2-hydroxy-3-(3-cyanophenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 339 (M-15,0.1), 234 (15), 233(100), 121 (21), 102 (7), 90 (6).

Compound 161:N-[2-hydroxy-3-(4-cyanophenoxy)propyl]-1,1-dimethyl-2-(4-methoxyphenyl)ethylamineHydrochloride; GC/EI-MS, m/z (rel. int.) 339 (M-15,1), 234 (16), 233(100), 163 (5), 121 (15), 102 (5).

Compound 166:N-[2R-Hydroxy-3-[(2-cyanobenzthien-3-yloxy)propyl]-1,1-dimethyl-2-(3,4,dichlorophenyl)ethylamine.Prepared as a hydrochloride salt, MS (ES) m/e 449 [M+H]⁺

Compound 167: R-1-[1,1 Dimethyl-2-(4-methoxyphenyl)ethylaminol-3-(2'-carbazoloxy)pran-2-ol. Prepared as a trifluoroacetatesalt, MS (ES) m/e 419.2 [M+H]⁺.

Compound 168:N-[2R-Hydroxy-3-[(2-bromopyridinyloxy)propyl]-1,1-dimethyl-2-(4-methoxy)ethylamine.Prepared as a hydrochloride salt, MS (ES) m/e 411,409 [M+H]⁺.

Compound 169: N-(2-hydroxy-3-(3-N,N-dimethylphenoxy)propyl)-1,1-dimethyl-2-(-4-methoxyphenyl)ethylamine, GC/MS 251(100),176(9), 163(5), 138(11), 137(6),(8), 125(10), 121(23), 114(46), 108(6),77(6), 76(7),(10), 70(14), 42(8).

Compound 170:N-(2-hydroxy-3-(3-phenylphenoxy)propyl)-1,1-dimethyl-2-(-4-methoxyphenyl)ethylamine.GC/MS (mt, 0.1), 284(100), 121(28), 285 (27), 152(13), 70(13), 71(11),153(10).

Other embodiments are within the following claims. Thus, while severalembodiments have been shown and described, various modifications may bemade, without departing from the spirit and scope of the presentinvention.

We claim:
 1. A method of treating a patient comprising the step ofadministering to said patient a therapeutically effective amount of acalcilytic compound having the formula: ##STR87## wherein R₁ is selectedfrom the group consisting of: aryl, longer-length alk, and cycloalk;R₂is selected from the group consisting of: lower alk, cycloalk, alkoxy,H, OH, ═O, C(O)OH,. C(O)O-lower alk, C(O)NH-lower alk, C(O)N(loweralk)₂, SH, S-lower alk, NH₂, NH-lower alk, and N(lower alk)₂ ; R₃ and R₄is each independently lower alk or together cyclopropyl; R₅ is aryl; R₆if present is either hydrogen, lower alkyl or lower alkenyl, wherein R₆is not present if R₂ is ═O; Y₁ is lower alkylene; Y₂ is methylene; Y₃ islower alkylene; Z is selected from the group consisting of: O, S, oralkylene; or a pharmaceutically acceptable salt or complex thereof;wherein said patient has a disease or disorder characterized by one ormore of the following: (1) an abnormal bone or mineral homeostasis; (2)an abnormal amount of an extracellular or intracellular messenger whichis ameliorated by a compound able to effect one or more calcium receptoractivities; or (3) an abnormal effect of an intracellular orextracellular messenger which is ameliorated by a compound able toaffect one or more calcium receptor activities.
 2. The method of claim1, wherein said disease or disorder is characterized by said abnormalbone or mineral homeostasis.
 3. The method of claim 1, wherein saiddisease or disorder is selected from the group consisting of:osteosarcoma, periodontal disease, fracture healing, osteoarthritis,rheumatoid arthritis, Paget's disease, humoral hypercalcemia malignancy,and osteoporosis.
 4. The method of claim 3, wherein disease or disorderis osteoporosis.
 5. A method of treating a patient comprising the stepof administering to said patient an amount of a calcilytic compoundsufficient to increase serum PTH level, said compound having theformula: ##STR88## wherein R₁ is selected from the group consisting of:aryl, longer-length alk, and cycloalk;R₂ is selected from the groupconsisting of: lower alk, cycloalk, alkoxy, H, OH, ═O, C(O)OH,C(O)O-lower alk, C(O)NH-lower alk, C(O)N(lower alk)₂, SH, S-lower alk,NH₂, NH-lower alk, and N(lower alk)₂ ; R₃ and R₄ is each independentlylower alk or together cyclopropyl; R₅ is aryl; R₆ if present is eitherhydrogen, lower alkyl or lower alkenyl, wherein R₆ is not present if R₂is ═O; Y₁ is lower alkylene; Y₂ is methylene; Y₃ is lower alkylene; Z isselected from the group consisting of: O, S, or alkylene; or apharmaceutically acceptable salt or and complex thereof.
 6. The methodof claim 5, wherein said method causes an increase in serum PTH having aduration of up to one hour.
 7. The method of claim 5, wherein saidmethod causes an increase in serum PTH having a duration of one totwelve hours.
 8. The method of claim 7, wherein said duration is abouttwo to about four hours.
 9. The method of claim 5, wherein said methodcauses an increase in serum PTH up to 0.5 fold greater than peak serumPTH in said patient.
 10. The method of claim 5, wherein said methodcauses an increase in serum PTH 0.5 fold to 5 fold greater than peakserum PTH in said patient.
 11. The method of claim 5, wherein saidmethod causes an increase in serum PTH 5 fold to 10 fold greater thanpeak serum PTH in said patient.
 12. The method of claim 5, wherein saidmethod causes an increase in serum PTH at least 10 fold greater thanpeak serum PTH in said patient.
 13. The method of any one of claims1-12, wherein R₅ is either an optionally substituted phenyl or anoptionally substituted naphthyl.
 14. The method of claim 13, wherein R₁is aryl;Y₁ is methylene; Y₂ is methylene; Y₃ is methylene: and Z iseither O, S, NH, or unsubstituted alkylene.
 15. The method of claim 14,whereinR₂ is OH or alkoxy, R₆ is hydrogen, and Z is either O, S, orunsubstituted alkylene.
 16. The method of claim 15, whereinR₂ is OH ormethoxy, and R₃ and R₄ is each independently a lower alkyl.
 17. Themethod of claim 16, wherein Z is O or methylene, R₂ is OH, R₃ is methylor ethyl; and R₄ is methyl or ethyl.
 18. The method of claim 17, whereinR₅ is a substituted phenyl having one to four substituents eachindependently selected from the group consisting of: methoxy, loweralkyl, OCF₃, CFH₂, CHF₂, CF₃, OCH₂ CF₃, F, Cl, Br, I, OH, SH, CN, NO₂,NH₂, methylene dioxy, NH-lower alkyl, N(lower alkyl)₂, C(O)lower alkyl,S-lower alkyl, S(O)lower alkyl, S(O)₂ lower alkyl, OC(O)lower alkyl,SC(O)lower alkyl, OC(S)lower alkyl, NHC(O)lower alkyl, N(loweralkyl)C(O)lower alkyl, NHC(S)lower alkyl, N(lower alkyl)C(S)lower alkyl,NHS(O)lower alkyl, N(lower alkyl)S(O)lower alkyl, C(O)OH, C(O)O-lowerallyl, C(O)NH₂, C(O)NH-lower alkyl, C(O)N(lower alkyl)₂, S(O)₂ NH₂,S(O)₂ NH-lower alkyl, and S(O)₂ N(lower alkyl)₂.
 19. The method of claim18, wherein each R₅ substituent is independently selected from the groupconsisting of: methoxy, lower-haloalkyl, S-lower alkyl,lower-haloalkoxy, lower alkyl, lower alkenyl, halogen, SH, CN, NO₂, NH₂and OH.
 20. The method of claim 19, wherein R₅ is a substituted phenylwith at least one substituent in a meta or para position selected fromthe group consisting of: lower alkyl, methoxy, Cl, F, Br, and lowerhaloalkoxy, provided that said R₅ substituted phenyl may also have 2 to3 additional substituents.
 21. The method of claim 19, wherein R₁ iseither an optionally substituted phenyl, an optionally substitutedpyridyl, an optionally substituted benzothiopyranyl, or an optionallycarbazole.
 22. The method of claim 21, wherein R₁ is a substitutedphenyl having one to four substituents each independently selected fromthe group consisting of: alkoxy, lower-haloalkyl, S-lower alkyl,lower-haloalkoxy, lower alkyl, lower alkenyl, halogen, SH, CN, NO₂, NH₂,OH and sulfamoyl.
 23. The method of claim 22, wherein R₁ is either2-CN-phenyl, 2,3-dichloro phenyl, 2-nitro-phenyl,2-cyano-3-chloro-phenyl or 2,3-dichloro-4-sulfamoyl-phenyl.
 24. Themethod of claim 17, wherein R₅ is a substituted naphthyl having one tofour substituents each independently selected from the group consistingof: alkoxy, lower-haloalkyl, S-lower alkyl, lower-haloalkoxy, loweralkyl, lower alkenyl, halogen, SH, CN, NO₂, NH₂ and OH.
 25. The methodof claim 24, wherein R₁ is a substituted phenyl having one to foursubstituents each independently selected from the group consisting of:alkoxy, lower-haloalkyl, S-lower alkyl, lower-haloalkoxy, lower alkyl,lower alkenyl, halogen, SH, CN, NO₂, NH₂, OH and sulfamoyl.
 26. Themethod of claim 17, wherein R₅ is naphthyl.
 27. The method of claim 26,wherein R₁ is either an optionally substituted phenyl, an optionallysubstituted pyridyl, an optionally substituted benzothiopyranyl, or anoptionally carbazole.
 28. The method of claim 27, wherein R₁ is asubstituted phenyl having one to four substituents each independentlyselected from the group consisting of: alkoxy, lower-haloalkyl, S-loweralkyl, lower-haloalkoxy, lower alkyl, lower alkenyl, halogen, SH, CN,NO₂, NH₂, OH and sulfamoyl.
 29. The method of claim 28, wherein R₁ iseither 2-CN-phenyl, 2,3-dichloro phenyl, 2-nitro-phenyl,2-cyano-3-chloro-phenyl or 2,3-dichloro-4-sulfamoyl-phenyl.
 30. Themethod of claim 14, wherein said compound is selected from the groupconsistingof:(R)-N-(2-hydroxy-3-(3-chloro-2-cyanophenoxy)propyl)-1,1-dimethyl-2-(4-methoxypheny)ethylamine;(R)-N-(2-hydroxy-3-((2,3-dichloro-4-dipropylsulfamoyl)phenoxy)-1-propyl)-N-(1,1-dimethyl-2-(4-methoxyphenyl)ethyl)amine;N-(2-hydroxy-3-phenoxypropyl)-1,1-dimethyl-2-(2-naphthyl)ethylamine;(R)-N-(2-hydroxy-3-(2,3-dichlorophenoxy)propyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine;(R)-N-(2-hydroxy-3-(2-cyanophenoxy)propyl)-1,1-dimethyl-2-(4-methoxyphenyl)-ethylamine;andN-(2-hydroxy-3-(2-nitrophenoxy)propyl)-1,1-dimethyl-2-(4-methoxyphenyl)ethylamine;or a pharmaceutically acceptable salt or complex thereof.